Design of Cocrystals for Molecules with Limited Hydrogen Bonding Functionalities: Propyphenazone as a Model System

Abstract

ABSTRACT:We report eight new cocrystals with an analgesic drug, propyphenazone, which belongs to a family of compounds that possess limited or no hydrogen bonding functionality. Such molecules 2 present difficulties in predicting and selecting appropriate coformers for potential multicomponent systems, and current prediction methodologies are unsuitable due to their focus around hydrogen bonding. This study used a knowledge-based strategy to identify appropriate coformers as well as testing a wide variety of molecules to confirm the initial predictions. All new cocrystals were characterized using X-ray diffraction techniques as well as measuring their physiochemical properties. These included the thermal behavior, stability under slurry and accelerated conditions, solubility and dissolution rate and were compared with the parent propyphenazone. It was found that while the stability of most of the cocrystals and propyphenazone was comparable, a cocrystal with hydroquinone showed an increase in both the solubility and dissolution rate of propyphenazone.

Cocrystals of Leflunomide: Design, Structural, and Physicochemical Evaluation

“…These include hydrogen bond propensity calculations (HBPCs), 18 and similar twostage rational selection of coformers based on structural diversity, 19 and the use of known structurally similar compounds to enable the identification of appropriate coformers for cocrystal screening. 20,21 Leflunomide (5-methyl-N-[4-(trifluoromethyl) phenyl]-isoxazole-4-carboxamide, LEF, Figure 1) is an immunosuppressive disease-modifying antirheumatic drug that is used to slow down progression of the rheumatoid arthritis through inhibition of pyrimidine synthesis. 22 It is formulated as Arava  , and is converted into its active metabolite, Teriflunomide in vivo.…”

X-Ray Crystallography and its Role in Understanding the Physicochemical Properties of Pharmaceutical Cocrystals

“…A plausible solution to address this issue is to use knowledge-based methods, which incorporate structural, geometrical, and chemical information pertaining to the API and coformers. 59 The recent developments in cocrystal research suggest reliable pathways to identify suitable solid forms for development of novel drug formulations. In this regard, crystal structures deposited in the CSD serve as valuable source of information for the design of functional cocrystals.…”

Insights into the structure-property relationship of pharmaceutical co-crystals: Charge density and quantum chemical approaches

“…As described in our previous study, [25] each co-crystal exhibits a primary O-H•••O hydrogen bond between the co-former hydroxyl or carboxylic acid functional group and PROPY and this can be assessed using two approaches. Study of the molecular graph in conjunction with the molecular pair analysis shows that this interaction dominates the strongest PROPY•••co-former interaction.…”

“…A selection of our own work in this area includes a comprehensive co-crystal design, screen, and structural and physicochemical property analysis on an API with antipyretic and analgesic effectspropyphenazone (1,5-dimethyl-2-phenyl-4-propan-2-yl-pyrazol-3-one, PROPY). [25] An interaction analysis of similar structures in the Cambridge Structural Database (CSD) [26] led to a co-crystal screen involving 90 co-formers which generated 15 putative new co-crystals and 8 novel co-crystal single crystal structures. Analysis of API•••co-former interactions in the atomic resolution crystal structures led to some correlations with trends in physical properties such as stability, solubility and dissolution rate.…”