Synthesis of Aliphatic Polyanhydrides with Controllable and Reproducible Molecular Weight

Abstract

Polyanhydrides have been synthesized for decades by melt-polycondensation of diacid monomers and 5 to >10 times mole excess acetic anhydride to diacid monomers to form polymers with a polydispersity ranging from 2.5 to 6 and low reproducibility. Hydrophobic segments in polyanhydrides are beneficial to hinder the characteristic hydrolytic cleavage of an anhydride bond that provides stable polyanhydrides at room temperature. The objective of this work is to synthesize aliphatic polyanhydrides with various hydrophobic segments, controllable and reproducible molecular weight, and low polydispersity that are essential for potential use as drug carriers. A series of polyanhydrides of suberic, azelaic, sebacic, and dodecanedioic acids with controlled molecular weight, reduced polydispersity, and standard deviation of molecular weights, have been synthesized. All synthesized polyanhydrides were thoroughly characterized by NMR, Fourier transform infrared spectroscopy, and gel permeation chromatography. Molecular weights of the synthesized polyanhydrides are highly controllable, depending on the degree of activation of the dicarboxylic acid monomers, i.e., the amount of acetic anhydride used during synthesis. Polyanhydrides have been synthesized in triplicate by melt-polycondensation, using various mole ratios of acetic anhydride to diacids. The standard deviation of the molecular weights of the polyanhydrides is minute when using 1 equivalent of acetic anhydride during the activation of dicarboxylic acids, whereas if excess acetic anhydride is used, the standard deviation is very high. The effect of safe and natural inorganic catalysts, Calcium oxide, Zinc oxide, and Calcium carbonate on polymerization is also studied. As-synthesized poly(sebacic acid) can offer convenience to use in controlled drug delivery applications. In vitro drug release study using Temozolamide (TMZ), a medication used to treat brain tumors such as glioblastoma and anaplastic astrocytoma, shows 14% TMZ release after the first hour and 70% release over one day from the poly(sebacic acid) wafers.

Polyanhydride Chemistry

“…In addition, the poly(SA) also used as a carrier to study the in vitro release pattern of the anticancer drug Temozolomide (TMZ) in the acetate buffer solutions (pH = 3.5) at 37 °C. 55 Toward the development of novel aliphatic PAs for biomedical applications, the recent highlights made in this section are further summarized as follows:…”

“…Therefore, it is essential to maintain the controlled and reproduced molecular weights of the polymer for medical usage. Therefore, our group studied the proof of concept to get the controlled molecular weight of the aliphatic PAs (poly­(suberic acid), poly­(azelaic acid), poly­(sebacic acid), and poly­(dodecanedioic acid)) with varying acetic anhydride concentrations . An increase in the polymer molecular weight is dependent on the concentration of the acetic anhydride used.…”

“…The nanoparticles are less toxic at lower concentrations as revealed by concentration-dependent cell toxicity studies. In addition, the poly­(SA) also used as a carrier to study the in vitro release pattern of the anticancer drug Temozolomide (TMZ) in the acetate buffer solutions (pH = 3.5) at 37 °C …”

“…The inclusion of hydrophobic units alternatively and placing them adjacent to the anhydride bond controls the degradation rate. ,, The hydrophobic chain shields the anhydride bond, thus controlling its cleavage from water in such a way stable PAs could be developed. ,,, The problem associated with poor drug encapsulation efficacy, stability and drug release kinetics of microspheres/nanoparticles is also addressed by increasing their hydrophobicity . One significant approach is the use of biocompatible fatty acids as hydrophobic monomer segments during the PA synthesis; this can lead to room temperature stable PAs with low melting nature. ,,, In addition, the degraded metabolites of fatty acid-based PAs are eco-friendly to the body and can be easily eliminated. The development of novel synthetic methodologies based on the use of eco-friendly metal-based catalysts (example: CaO, Ca­(OH) 2 , and CaCO 3 ), optimizing the concentration of acetic anhydride ratios, reaction time, temperature, etc.…”

“…Numerous improvements, though, have been made in PA chemistry to overcome these limitations. One of the significant developments made in this field is the finding of poly­(ester-anhydrides). − The incorporation of ester into the PA backbone helps to enhance the shelf life of the resultant poly­(ester-anhydrides). ,,, In these polymers, the ester-based hydrophobic nonlinear side chain such as hydroxy alkanoic acids shields the anhydride bond. This controls the cleavage of the anhydride linkage from moisture and provides stable polymers.…”