Engineering Reaction and Crystallization and the Impact on Filtration, Drying, and Dissolution Behaviors: The Study of Acetaminophen (Paracetamol) by In-Process Controls

Abstract

Acetaminophen was synthesized by reacting p-aminophenol with acetic anhydride. Overall materials balance was compiled. Three different crystallization paths (i.e., cases I, II, and III) involving various modes in agitation and addition of sodium hydroxide were taken to produce acetaminophen particles with different particle size distributions (PSDs) and polymorphism. The concentration profile of acetaminophen, temperature, and pH values throughout reaction and crystallization were monitored mainly by in-process control (IPC). The rates of nucleation, crystal growth, and agglomeration during crystallization were quantified by the mixed-suspension mixed-product removal (MSMPR) formalism. The average specific cake resistance for filtration, Krischer rate-moisture plot for drying, Carr's index for powder flowability, and dissolution rate for drug delivery of acetaminophen crystals generated in cases I, II, and III were thoroughly studied and compared. ■ INTRODUCTIONIsolation and purification of solid intermediates and final product from chemical reaction are often achieved by crystallization followed immediately afterwards. 1−3 Reaction crystallization can be thought of as a bottom-up fabrication 4,5 spanning over an enormous time and length scale 6 from the production of angstrom leveled molecules to the generation of nanometer sized nuclei and the growth of submicrometer-sized primary crystals, and all the way up to the generation of micrometer-sized agglomerates. Besides the reaction-related factors such as the completion of reaction, the impurity profiles and levels, and the optimization of yield, 7 other significant engineering impacts brought about by the solid state properties of the final crystallization product, such as polymorphism, 8 crystal habit, particle size, and distribution, 9 on the downstream behaviors 10 involving filter cake resistance, 9,11 drying kinetics, 12 flowability, 13,14 and dissolution rate 5 should be fully considered for ensuring rugged and reproducible scale-up operations. Many of the previous efforts have already been placed on those separate areas, for example: (a) chemical preparation, 15,16 (b) impurity effect on crystallization kinetics, 17 (c) crystallization route on polymorphism, 18,19 (d) solvent selection on crystal habits and agglomerates, 20−22 (e) agitation speed and antisolvent feeding rate on agglomeration, 23 (f) different types of crystallizers on crystal size distribution (CSD), 24 (g) optimization of particle size distribution (PSD), 25 (h) prediction on agglomerate type, 26 (i) rates of nucleation, growth, and aggregation, 27,28 (j) spherical agglomeration, 29 (k) drying of drug substances, 30,31 and (l) crystal growth kinetics and dissolution behavior. 32,33 However, making stable and reproducible pharmaceutical products required monitoring and controlling of the desired PSD from crystallization all the way through various agitated dryers. 34,35 The collective behaviors manifested by different PSDs in blending, wet granulation, and dissolution have also been inve...

Reactive Crystallization of Paracetamol in a Continuous Oscillatory Baffled Reactor

“…Since it was first synthesized by Morse in 1878, the method of paracetamol production has gone through changes in order to enhance its productivity and properties. For example, acetaminophen can be synthesized from 4- hydroxyacetophenone, − nitrobenzene, − 4-nitrophenol, − and 4-amniophenol. , The one-step acylation of 4-aminophenol has attracted increasing attention because of its simple operating conditions, − and paracetamol crystals are normally separated and purified via a recrystallization process. , Extensive work on the recrystallization of paracetamol has previously been reported using cooling − and antisolvent means. − Once again, there are few studies in the literature on reactive crystallization in a continuous process. The closest one is the work by Agnew et al, , who reported selective access to produce a metastable solid form of paracetamol in a COBR by adding metacetamol as a template molecule.…”

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

“…Strategically, the two separate events of crystallization and SA can be orchestrated to tune the majority of round granules to fall mainly in the range of 250–2000 μm at will which is difficult to achieve by conventional methods, such as seeding, within a reasonable batch time. The absence of filtration and drying steps between the nonstop action of crystallization and SA steps during the three-in-one intensified process also allows the favorable production of small sized crystals in the crystallization step without worrying that they would create any high wet cake resistance in filtration or powder lumping in drying, which usually take place after the crystallization step . In the three-in-one intensified process, the reaction conversion, crystal yield, agglomerate yield, the purity levels in the solution and solid phase, granular flowability, friability, strength, tabletability, and dissolution rate will be fully investigated.…”

“…The absence of filtration and drying steps between the nonstop action of crystallization and SA steps during the three-in-one intensified process also allows the favorable production of small sized crystals in the crystallization step without worrying that they would create any high wet cake resistance in filtration or powder lumping in drying, which usually take place after the crystallization step. 33 In the three-inone intensified process, the reaction conversion, crystal yield, agglomerate yield, the purity levels in the solution and solid phase, granular flowability, friability, strength, tabletability, and dissolution rate will be fully investigated. Finally, to pave the way for scaling up the three-in-one intensified process for dimethyl fumarate in the future, a 10 L sized vessel will be used to prove the feasibility as well.…”

Particle Engineering of an Active Pharmaceutical Ingredient for Improved Micromeritic Properties

“…Crystal‐habit modification has been investigated in the light of influencing the purification behavior , compressibility, and cake resistance during filtration and drying , , cohesion of powders , behavior during jet milling , as well as during extrusion processes , tableting behavior , , and finally wettability and dissolution rates .…”