Round Granules of Dimethyl Fumarate by Three-in-One Intensified Process of Reaction, Crystallization, and Spherical Agglomeration in a Common Stirred Tank

Abstract

Pure, isomorphic, round, and free-flowing dimethyl fumarate granules in a size range of 250−2000 μm were successfully produced directly from esterification through the three-in-one intensified process of three distinctive steps of reaction, crystallization, and spherical agglomeration (SA) in a 0.5 L sized jacketed glass stirred tank. Dimethyl fumarate was prepared by sulfuric acid catalyzed esterification of fumaric acid with methanol. The reaction temperature was below the maximum allowable limit of 65 °C as determined by reaction kinetics to avoid the runaway situation. The dissolution rate of primary crystals of dimethyl fumarate was inversely proportional to the particle size which was strongly affected by the antisolvent addition and temperature cooling schemes during crystallization. However, the dissolution rate of the round granules was mainly dependent on the exterior dimension of the granules and not so much on the primary crystal size inside the granules. The mechanical properties such as density, porosity Carr's index, friability, and fracture force of round dimethyl fumarate granules generated in (1) three-in-one processes with the final temperatures at either 5 or 25 °C (Three-in-one I and II) and ( 2) SA of dimethyl fumarate, which was done separately and disconnected from the train of reaction and crystallization process at either 5 or 25 °C (SA I and II), were thoroughly studied and compared. The concept of scale-up for Three-in-one I and II was also verified in a 10 L sized jacketed glass stirred tank. Powder manufacturability such as flowability, blend uniformity, and compressibility had been substantially enhanced by spherical agglomeration. The added values of free-flowing and easy-to-pack properties to dimethyl fumarate in addition to its original intrinsic slip planes in the crystal lattice would make direct compaction into tablets feasible.

Effect of Superimposed Vibrations on Droplet Oscillation Modes in Prilling Process

“…Theoretical studies of the process of liquid jet decay into droplets under the action of its own oscillations [6] is the first, major step of theoretical and experimental studies to develop reliable mathematical models and to create calculation techniques for designing prillers. These models should spray the liquid into prills [7] with subsequent crystallization [8]. Moreover, the study of physical processes that affect the size of droplets allows designing new prillers to obtain monodisperse granules [8].…”

“…These models should spray the liquid into prills [7] with subsequent crystallization [8]. Moreover, the study of physical processes that affect the size of droplets allows designing new prillers to obtain monodisperse granules [8]. In this regard, the theoretical description of the liquid jet motion is based on jet theory [9,10].…”

Encapsulation of Synthesized Plant Growth Regulator Based on Copper(II) Complex in Chitosan/Alginate Microcapsules

“…The first two phase transitions are described with the formation of endothermic peaks at 94.6 °C and 108.1 °C. The formation of a rather broad peak at 94.6 °C and the formation of peak shoulder could be an indication of the overlapping effect of the loss of free water and solid-solid transition of dimethyl fumarate, to a phase that melts at 108.1 °C [ 31 ]. Endothermic peaks at 141.4 °C and 161.8 °C are most probably associated with loosing of crystal water molecules.…”

Effects of Scale-Up and Impeller Types on Spherical Agglomeration of Dimethyl Fumarate

“…It is possible to directly connect SA with a chemical synthesis of API. 5 The SA method was chosen in this study because of its low cost, simplicity, and high flexibility.…”

“…4 At the transition period, additional investment should be considered for the vast disposal of batch processing equipment and staff training. 5 Also, the design for continuous (crystallization) processes is more difficult since all parameters are interplaying in the processes. Up to date, the development of continuous processes in the pharmaceutical industry is restricted to other separate steps and disconnected unit operations, including API synthesis, filtration, drying, milling, blending, and granulation, when existing theories or knowledge for these batch unit operations has long been understood.…”