Search

The conventional approach for developing any polymeric biomaterial is to follow protocols available in the literature and/or perform trial-and-error runs without a scientific basis. Here, we propose an analysis of a complex overlay of molecular interactions between drugs and polymers that provides a strategic pathway for biomaterial development. First, this work provides an innovative interaction-based method for developing an ocular formulation involving in situ gelling chitosan, gelatin, and glycerophosphate systems. A systematic interaction study is conducted based on the measurement of hydrodynamic radius, zeta potential, and viscosity with the sequential addition of formulation components. The increase in the hydrodynamic radius of the polymer with the addition of drugs can be interpreted as better diffusion of the drug inside the charged polymer chains and vice versa. Based on the knowledge of these interactions, a formulation has been designed that shows better drug release results with extended and sustained release compared to literature protocols, hence accentuating the importance of this study. An in-depth analysis of interactions can lead to a better understanding of the system. Second, we demonstrate the development of two dual-drug biomaterial systems, i.e., an in situ gelling and a liquid formulation at ocular surface temperature from the same polymers, which can be used as an ocular antiglaucoma formulation. Prior knowledge of the interactions between the drug polymers can be used to design a better formulation. The demonstrated application of this interaction-based protocol development can be extended universally to any biomaterial. This would provide a comprehensive idea about the properties and interactions of polymers and drugs, which can also serve as a base/starting point for a new formulation/biomaterial development.

Graphical abstract:

The effect of salt on the static properties of aqueous solution of gelatin is studied by molecular dynamics simulation at pH = 1.2, 7, and 10. At the isoelectric point (pH = 7), a monotonic increase in size of the polymer is obtained with the addition of sodium chloride ions. In the positive polyelectrolyte regime (pH = 1.2), collapse of gelatin is observed with increase in salt concentration. In the negative polyelectrolyte regime, we observe an interesting collapse–reexpansion behavior. This is due to the screening of repulsion between the excess charges followed by the screening of attraction of oppositely charged ions as the salt concentration is increased. This mechanism is very different from the charge inversion mechanism which causes the reexpansion in the presence of multivalent ions. The location of salt concentration corresponding to the minimum size of the chain is comparable to the theoretical estimate. The shift in the peak of radial distribution function calculated between monomers and salt ions confirms this spatial reorganization. The predictions from the simulation are verified by dynamic light scattering(DLS) and small-angle X-ray scattering (SAXS) experiments. The size of the hydrodynamic “clusters” obtained from DLS confirms the simulation predictions. Persistence length of the gelatin is calculated from SAXS to get single chain statistics, which also agrees well with the simulation results.

Industrial scale process modelling and optimization of long chain branched polymer reaction network is currently an area of extensive research owing to the advantages and growing popularity of branched polymers. The highly complex nature of these reaction networks requires a large set of stiff ordinary differential equations to model them mathematically with adequate precision and accuracy. In such a scenario, where execution time of model is expensive, the idea of making the online optimization and control of these processes seems to be a near impossible task. Catering to these problems in the ongoing research, the authors presented a novel work where the kinetic model of long chain branched poly vinyl acetate has been utilized to find the optimum processing conditions of operation using Sobol sequence based ANN as meta models in a fast and highly efficient manner. The article presents a novel generic algorithm, which not only disables the heuristic approach of designing the ANN architecture but also allows the computationally expensive first principle model to determine the configuration of the ANN which can emulate it with maximum accuracy along with the size of training samples required. The use of such a fast and efficient Sobol based ANN as surrogate model obtained by the proposed algorithm makes the optimization process 10 times faster as compared to a case where optimization is carried out with the expensive first principle model.

A kinetic model has been proposed for a binary catalyst system with the available experimental data from the open literature, in which one catalyst produces polypropylene macromonomer, while the other catalyst attacks the macromonomers as side chains to the isotactic polypropylene backbone. After validating the model with the experimental data, it has been extended to find the optimal process conditions for the desired combination of conflicting objectives that leads to manufacturing of polymer with controlled branching suitable for varied kind of applications. A well-established multi-objective optimization technique, NSGA II, has been utilized for this purpose. Some of the Pareto optimal points are found to be better than the experimental data and show improvement in process performance.

Glaucoma is one of the leading causes of loss of vision. The problems associated with the marketed formulations of anti-glaucoma drugs are low bioavailability, unwanted side effects, and low patient compliance. Hydrogels are an important class of soft materials that play a crucial role in developing an ocular drug delivery system. They assume a special significance in addressing the problems associated with the marketed formulations of eyedrops. An appropriate design of the hydrogel system capable of encapsulating single or multiple drugs for glaucoma has emerged in recent times to overcome such challenges. Although various modes of imaging play critical roles in assessing the efficacy of these formulations, evaluating hydrogels for drug permeation and retention remains challenging. Especially, the assessment of dual drugs in the hydrogel system is not straightforward due to the complexity in measuring drug penetration and retention for in vivoor ex vivosystems. There is a need to develop tools for the fabrication and validation of hydrogel-based systems that give insight into precorneal retention, biocompatibility, cellular uptake, and cell permeation. The current review highlights some of the complexities in formulating hydrogel and benchmarking technologies, including confocal laser scanning microscopy, fluorescent microscopy, slit-lamp biomicroscopy, and camera-based imaging. This review also summarizes recent evaluations of various hydrogel formulations using in vitroand in vivomodels. Further the article will help researchers from various disciplines, including formulation scientists and biologists, set up preclinical protocols for evaluating polymeric hydrogels.

Summary:TBOT is a proven catalyst for the esterification step of the PPT polymerization process. Previous studies have shown that the performance of TBOT is superior in terms of the enhanced degree of polymerization and shorter processing time. However, one interesting aspect which has not yet been investigated is whether with different process objectives, like by‐product minimization and controlled growth of desired functional groups, any other catalyst offers any increase in process performance. The present study gives a detailed process analysis through different sets of optimized operations, which consists basically of searching for other catalytic options for process improvements. A well validated kinetic model for the esterification step of the PPT polymerization process and the advanced Real‐Coded NSGA‐II optimization routine have been used in this study. It can be seen that with all the process considerations, such as maximization of the degree of polymerization, minimization of processing time and the enhanced controlled growth of desired functional groups and minimization of by‐products, the Zn‐based catalyst can replace the conventional Ti‐based catalyst. An Sn‐based catalyst was also found to be able to compete with these two catalysts in some cases.

Summary:A well‐validated kinetic scheme has been studied for PPT, poly(propylene terephthalate) polymerization process in batch and semi‐batch mode with tetrabutoxytitanium (TBOT), a proven catalyst. Optimization study and analysis for PPT are rare, as the industrial relevance of PPT just became vibrant due to the commercial availability of one of its monomers in industrial scale in the recent past. Correctness of the analysis is checked by a new approach and parameters for the model are estimated from available experimental data. Solubility of terephthalic acid (TPA) is less in reaction medium and this effect is also considered along with the reaction scheme. Several simulations have been performed to see various process dynamics and this ultimately helps in formulating optimization problems. Using recently developed and well tested real‐coded non‐dominated sorting genetic algorithm‐II, a state‐of‐the art evolutionary optimization algorithm, a couple of three objective optimization problems have been solved and corresponding Pareto sets are presented. Results show remarkably promising aspects of productivity enhancement with an improvement in product quality. Sensitivity analysis for relatively uncertain solubility parameter is also performed to estimate its effect over the proposed optimal solutions.

Summary:An epoxy polymerization process is studied in semi‐batch mode. Caustic has a very critical influence on epoxy polymerization process, which is modeled as a set of highly nonlinear coupled ODE's (ordinary differential equations). Owing to the highly complicated, nonlinear domain of analysis, “Differential Evolution (DE)” and “Genetic Algorithm (GA)” are used as optimization tools to identify the $\overline M _{\rm n}$‐PDI Pareto set and study the best operating strategy with respect to NaOH addition. The moment of various oligomeric components during the semi‐batch polymerization is also presented for a better understanding of the process. This study demonstrates the potential of evolutionary optimization algorithm to identify various operating philosophies of a semi‐batch epoxy reactor for a targeted product quality.

Summary: An epoxy polymerization process is studied in semi-batch mode. Caustic has a very critical influence on epoxy polymerization process, which is modeled as a set of highly nonlinear coupled ODE's (ordinary differential equations). Owing to the highly complicated, nonlinear domain of analysis, “Differential Evolution (DE)” and “Genetic Algorithm (GA)” are used as optimization tools to identify the $\overline M _{\rm n}$-PDI Pareto set and study the best operating strategy with respect to NaOH addition. The moment of various oligomeric components during the semi-batch polymerization is also presented for a better understanding of the process. This study demonstrates the potential of evolutionary optimization algorithm to identify various operating philosophies of a semi-batch epoxy reactor for a targeted product quality. Pareto plot for epoxy polymerization process with intermediate NaOH addition varying from 0.0 to 1.0 kmol · m⁻³.

Amphotericin B (AmB) is one of the potent antimycotic drugs used to cure invasive fungal infections and Leishmaniasis. However, it’s appalling collateral toxicity restricts its applicability for only parenteral administration with frequent dosing. Further, AmB is amphipathic and exhibits negligible absorption during oral administration due to its poor solubility. Current research unfolds the possibility to deliver AmB in a controlled way through oral route. First, homogeneous solution of gelatin-AmB was successfully electrospun into the nanofibers followed by crosslinking and compression to form compressed nanofibrous oral tablet (CNOT) containing 20 mg AmB in a 500 mg tablet. In-vitro biodegradation and thermal stability were investigated followed by studying the drug release kinetics. Antifungal activity was also examined up to seven days. AmB loaded CNOT showed zero order release profile with prominent antifungal activity up to seven days against Candida albicans. This study paves the way for a safe, yet effective oral administration of AmB while still maintaining the therapeutic efficacy for treating life-threatening fungal infections.