Development of integrated continuous pharmaceutical technologies

Thesis findings

1. Acetylsalicylic acid (ASA) was synthesized in continuous flow reactors for the first time. Design of experiment studies were conducted in order to optimize the two synthetic steps: i.e. the acetylation of salicylic acid (SA) and the quenching of impurities. By applying the allocated optimal conditions high yield and purity was achieved (>95% ASA and <3% SA). The second, quenching step was optimized both with and without a dissolved polymer excipient, thus the final reaction mixture was ready for direct further processing using either electrospinning or continuous crystallization. [I, XIV, XVI, XVII, XIX]

2. Electrospinning (ES) was applied as an advanced solvent removal tool for the direct processing of a flow reaction mixture for the first time. By applying high voltage on the metal ES spinneret connected to the flow chemistry microreactors, the volatile components evaporated, and the API was embedded into amorphous nanofibers. This way the direct work-up of the reaction mixture was accomplished, and no solid-liquid separation was required before formulation. With appropriate air ventilation the amount of residual solvents could be reduced below the regulatory limits. [I, XIV, XVI, XVII, XIX]

3. We developed and applied an apparatus for the controlled collection of the electrospun product and for the continuous end-to-end production of an orally dissolving web (ODW) formulation. The acetylsalicylic acid-loaded fibers – produced directly from the flow reaction mixture – were collected on the surface of a water-soluble carrier film. The formed double-layered strip was conveyed further to a cutter mechanism and was cut into smaller dosage units ready for patient administration. The good content uniformity and low residual moisture content of the ODWs was confirmed during longer, 8-hour long operations of the system. [I, XIV, XVI, XVII, XIX]

4. The applicability of the developed continuous system was extended to the production of an ODW formulation containing a poorly water-soluble compound, carvedilol (CAR). ES of CAR-loaded nanofibers was optimized to obtain a stable process. The fibers were collected on the surface of a modified pullulan carrier: citric acid was incorporated into the film to act as pH modifier during dissolution tests. The immediate dissolution and disintegration of the created ODW formulation was confirmed under conditions modelling the oral cavity. The 4-hour long continuous production of CAR-loaded ODWs showed appropriate content uniformity and the residual solvent content of the fibers complied to the regulatory requirements when secondary drying was applied on room temperature. [II]

5. A “Mixed Suspension Mixed Product Removal” (MSMPR) continuous crystallization equipment was directly connected to a Continuous Filtration Carousel (CFC) device for the first time. Stable continuous operation was achieved within the integrated system after the two combined steps were optimized together, and free-flowing crystalline product with excellent quality was obtained at the end of the process. [III, IV, XV]

6. The effect of critical crystallization process parameters on the filtered product quality was determined for the first time in an integrated continuous crystallization-filtration system. We found that only the temperature affected the yield and the particle size of the filtered product, while both residence time and temperature had an impact on the moisture content. The size of the acetylsalicylic acid crystals did not affect the filtration procedure of the used continuous filtration carousel device. The crystals could be dried appropriately to obtain a crystal powder with good flowability, applicable in the following continuous downstream processes. [III, IV, XV]

7. A continuously filtered pharmaceutical material was further processed to continuous blending with microcrystalline cellulose, and to the production of conventional compressed tablets for the first time. The blending efficiency was monitored by an in-line NIR probe. The produced tablets showed very low variation in content uniformity based on at-line NIR and off-line HPLC measurements. Thus, the end-to-end manufacturing of the most widespread compressed tablet dosage form was accomplished for the first time on a proof- of concept level. [IV, XV]

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or continue reading here: Development of integrated continuous pharmaceutical technologies – Ph.D. Thesis by András Domokos – BUDAPEST UNIVERSITY OF TECHNOLOGY AND ECONOMICS DEPARTMENT OF ORGANIC CHEMISTRY AND TECHNOLOGYGEORGE A. OLAH DOCTORAL SCHOOL

Excipients used in the experimental part of the thesis: Polyvinylpyrrolidone K30 (Kollidon® 30), Polyoxyethylen sorbitan mono-oleat (Tween® 80),α-1,4-; α-1,6-glucan (Pullulan®), (2-Hydroxypropyl)-β- cyclodextrin (HPβCD), Citric acid, Microcrystalline cellulose (Vivapur® 200)