Understanding the Effects of a Polymer on the Surface Dissolution of Pharmaceutical Cocrystals Using Combined Experimental and Molecular Dynamics Simulation Approaches

Abstract

The molecular interactions between the surfaces of cocrystals [i.e., flufenamic acid and theophylline (FFA-TP), flufenamic acid and nicotinamide (FFA-NIC), and carbamazepine and nicotinamide (CBZ-NIC)] and the polymers [i.e., polyethyleneglycol (PEG), polyvinylpyrrolidone (PVP) and copolymer of vinylpyrrolidone (60%)/vinyl acetate (40%) (PVP-VA)] were investigated through combined experimental and molecular dynamics simulation approaches to resolve the mechanisms of cocrystal dissolution and precipitation. It was found that adsorption of the polymers on the surfaces of cocrystals might prevent the precipitation of the parent drug and alter the dissolution rate. The effect of polymers on precipitation could be determined by the cocrystal dissolution rate, the interactions of polymers with the surfaces of cocrystals, the characters of the noncovalent bonds formed between the polymers and the cocrystal surfaces, and the mobility and conformation of the polymers. The etching experiments of single cocrystals revealed that FFA-NIC and CBZ-NIC appeared as surface precipitation cocrystals while FFA-TP could lead to bulk precipitation. Both PVP and PVP-VA were good precipitation inhibitors for FFA-NIC and they could completely inhibit the recrystallization of FFA III on the surfaces of dissolving cocrystals. In addition, as the adsorption of the polymer was slower than dissolution rate of the cocrystals, PVP and PVP-VA could only partially inhibit the recrystallization of CBZ dihydrate on the surface of CBZ-NIC. While PEG had no inhibitory effect on the surface crystallization of FFA-NIC and CBZ-NIC, due to its weak

Artemisinin Cocrystals for Bioavailability Enhancement. Part 1: Formulation Design and Role of the Polymeric Excipient

“…A supersaturated solution concentration of the parent drug can be generated due to rapid dissolution of cocrystals, which is a key requirement for improved drug oral absorption . It is thus critical to include a polymeric excipient in the formulation as an inhibitor to prevent the parent drug crystallization and to maintain drug in solution in aqueous media for a sufficient length of time to allow absorption. − Selection of a polymeric excipient in a cocrystal formulation can be problematic because the interplay of the polymer with both the parent drug and coformer in solution could lead to erratic drug release performance in vitro or in vivo. , Therefore, a thorough understanding of the dissolution mechanisms of cocrystals and their possible interaction with the excipients and dissolution environments is required to guide preclinical formulation development. , …”

“…19,20 Therefore, a thorough understanding of the dissolution mechanisms of cocrystals and their possible interaction with the excipients and dissolution environments is required to guide preclinical formulation development. 21,22 The objective of this work was to design oral formulations of ART cocrystals, which can be used on an appropriate rodent model (i.e., mouse selected for in vivo study) to evaluate their preclinical pharmacokinetics for further development. A simple and effective formulation, which allows ART cocrystals suspended in solution to be administered to mice, was developed.…”

“…A single crystal was first mounted onto a coverslip using doublesided seal tape, where the studied face was up and exposed. The coverslip was then immersed for 2 min in a Petri dish which contained 20 mL of preheated (at 37 °C) 0.01 M pH 6.8 PBS in the absence or presence of the selected polymer as shown in ref 22. The coverslip was taken out from the solution after a predetermined time interval and the remaining solution on the crystal surface was removed with filter paper.…”

Combining Co-Amorphous-Based Spray Drying with Inert Carriers to Achieve Improved Bioavailability and Excellent Downstream Manufacturability

“…It is currently challenging to experimentally measure this interaction. The molecular interactions between drugs and carrier in solution can been investigated through molecular dynamics simulation approaches to reveal the mechanisms of drugs dissolution [43]. Compared with MCC, LM has more hydrogen bond donors, which can influence the supramolecular structure of SAC-VAL in solution phase.…”

Artemisinin Cocrystals for Bioavailability Enhancement. Part 2: In Vivo Bioavailability and Physiologically Based Pharmacokinetic Modeling

“…To maintain and improve the performance of the cocrystals, addition of a polymer may be required as a nucleation and/or crystal growth inhibitor to prevent parent drug crystallization. Selecting a suitable combination of a cocrystal and polymeric inhibitor is usually accomplished through trial-and-error tests in vitro . − Drug absorption is a highly complex process, which is dependent upon numerous factors, including the physicochemical properties of the drug, characteristics of the formulation, and interplay with the underlying physiological properties of the GI tract, for example, the pH environment and metabolic enzymes . These in vitro tests may not be sufficient to identify an optimal cocrystal from a range of coformers and/or polymeric inhibitors in the formulation because they cannot provide insights into all the mechanisms of GI absorption in vivo .…”