A Novel Aminomethacrylate-Based Copolymer for Solubility Enhancement—From Radical Polymer Synthesis to Manufacture and Characterization of Amorphous Solid Dispersions

Abstract

The present study covers the synthesis, purification and evaluation of a novel aminomethacrylate-based copolymer in terms of its suitability for improving the solubility and in vitro release of poorly water-soluble drug compounds. The new copolymer was synthesized by solvent polymerization with radical initiation and by use of a chain transfer agent. Based on its composition, it can be considered as a modified type of dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate “EUDRAGIT® E PO” (ModE). ModE was specifically developed to provide a copolymer with processing and application properties that exceed those of commercially available (co-)polymers in solubility enhancement technologies where possible. By varying the concentration of the chain transfer agent in the radical polymerization process, the molecular weight of ModE was varied in a range of 173–305 kDa. To evaluate the solubility-enhancing properties of ModE, a series of drug-loaded extrudates were prepared by hot melt extrusion using the novel—as well as several commercially available—(co-)polymers. These extrudates were then subjected to comparative tests for amorphousness, solubility-enhancing properties, storage stability, and drug release. Celecoxib, efavirenz, and fenofibrate were used as model drugs in all experiments. Of all the (co-)polymers included in the study, ModE with a molecular weight of 173 kDa showed the best performance in terms of desired properties and was shown to be particularly suitable for preparing amorphous solid dispersions (ASDs) of the three model drugs, which in a first set of dissolution experiments showed better release behavior under pH conditions of the fasting stomach than higher molecular weight ModE types, as well as a variety of commercially available (co-)polymers. Therefore, the results demonstrate the successful synthesis of a new copolymer, which in future studies will be investigated in more detail for universal application in the field of solubility enhancement.

Preparation of Solid Self-Nanoemulsifying Drug Delivery Systems (S-SNEDDS) by Co-Extrusion of Liquid SNEDDS and Polymeric Carriers—A New and Promising Formulation Approach to Improve the Solubility of Poorly Water-Soluble Drugs

“…Concluding from these observations on the release performance obtained when E-173 kDa was used in the S-SNEDDS technology, it can be assumed that the higher flexibility of the polymer chains in the E-173 kDa copolymer resulted in good solubilization of the drugs celecoxib, efavirenz, and fenofibrate, respectively. As already stated, the trend regarding an improved drug release performance of S-SNEDDS containing ModE with lower M w observed in the present study was in good agreement with that observed in a previous study [22]. In both studies, the drug release of celecoxib-, efavirenz-and fenofibrate formulations with the same drug dose was investigated.…”

“…A comparison of the rate and extent of drug release of the S-SNEDDS prepared from different ModE types showed that a higher M w or a higher T g of the ModE copolymer used resulted in a decrease, both in the rate and extent of celecoxib-, efavirenz-, and fenofibrate release within the test period of 120 min (Figures 1a, 2a and 3a). These observations correlate with those made when ModE was used in the preparation of ASD [22]. The observed effect of M w and T g on drug release performance (dissolution rate of the drug substance was inversely proportional with M w and T g of a copolymer) was also determined by Knopp et al [25], who studied polyvinylpyrrolidone-based ASDs incorporating the drug substance celecoxib.…”

“…Torque values > 200 Ncm typically correlated with a pronounced melt viscosity, which could complicate the processing by clogging the extruder die. Compared to a previous study in which drug-loaded ASDs were prepared and in which the same active ingredients and similar amounts of active ingredients were used [22], S-SNEDDS could be prepared at lower extrusion temperatures than the corresponding ASDs due to the plasticizing effect of the incorporated L-SNEDDS. This facilitated overall processing and resulted in substantially lower torque values than in the preceding study [22].…”

“…Compared to a previous study in which drug-loaded ASDs were prepared and in which the same active ingredients and similar amounts of active ingredients were used [22], S-SNEDDS could be prepared at lower extrusion temperatures than the corresponding ASDs due to the plasticizing effect of the incorporated L-SNEDDS. This facilitated overall processing and resulted in substantially lower torque values than in the preceding study [22]. Affinisol ® HPMC 100 LV was extruded at a lower screw speed than all other (co)polymers, as it would otherwise have clogged the extruder die or led to a loss of the integrity of the polymer when further increasing the extrusion temperature.…”

“…A further objective was to identify a (co)polymer that would enable the preparation of stable S-SNEDDS without impairing the release behavior and storage stability of the L-SNEDDS used and, if possible, even improve them further. In addition to commercially available (co)polymers already used in the field of HME, a particular focus was on the evaluation of different variants of a recently developed aminomethacrylate-based copolymer that differed in M w [22].…”