Application of process analytical technology for monitoring crystallization processes

U današnje moderno doba farmaceutske industrije, proces kristalizacije je jedan od najvažnijih procesa prilikom proizvodnje farmaceutika u čvrstom obliku, odnosno u obliku tableta, što je jedan od najpopularnijih oblika uzimanja lijekova. Također je to jedan od najvažnijih načina dobivanja čvrstih tvari u čistom obliku. U tehnologiji se raznovrsni oblici kristala koriste za dobivanje tvari u obliku kristala određenog oblika, boje i svojstava. Iz tog razloga, postoji stalna potreba za razvitkom novih tehnika i usavršavanja samog procesa kristalizacije kako bi se dobili što čišći i pravilniji oblici kristala. U ovom radu istraživani su procesi kristalizacije u cilju dobivanja triju polimorfnih formi (A, B i C) aktivne farmaceutske supstance omeprazola, koji je na tržištu poznat kao lijek za želučane bolesti. Procesi kristalizacije provedeni su prema procesnim uvjetima prikazanim u patentnim prijavama za pojedini polimorf. Provedena su tri seta eksperimenata priprave navedenih polimorfa: prva dva seta provedena su u mjerilu od 250 ml, a zadnji set eksperimenata uvećan je na volumen od 7 l u svrhu in-line praćenja procesa pomoću Ramanove spektroskopije za identifikaciju polimorfa te FBRM (Focused Beam Reflectance Measurement) uređaja koji daje uvid u dinamiku procesa. Granulometrijske karakteristike produkta (oblik, veličina i raspodjela veličina) okarakterizirane su skenirajućim elektronskim mikroskopom (Scanning Electron Microscopy, SEM) te metodom laserske difrakcije za određivanje raspodjele veličina kristala. U prva dva seta eksperimenata, metodom rendgenske difrakcije (XRD) potvrđene su polimorfne forme A, B i C. Prilikom uvećanja procesa XRD analizom kao i Ramanovom spektroskopijom identificirani su samo C polimorfi omeprazola bez obzira po kojem je postupku provedena kristalizacija. Dobiveni rezultati ukazuju na važnost optimiranja i parametriziranja industrijskih procesa kristalizacije te na utjecaj uvećanja procesa na karakteristike finalnog produkta.In the modern age of the pharmaceutical industry, the process of crystallization is one of the most important processes for producing pharmaceuticals in solid form or tablet form, which is one of the most popular forms of drug taking. It is also one of the most important ways of obtaining solid substances in pure form. In the technology, various forms of crystals are used to obtain the crystalline substance of a particular shape, color and properties. For this reason, there is a constant need for developing new techniques and perfecting the crystallization process itself in order to obtain as clear and correct forms of crystals as possible. In this work, crystallization processes were investigated in order to obtain three polymorphic forms (A, B and C) of the active pharmaceutical substance omeprazole, on the market also known as a gastric disease drug. Processes of crystallization were carried out according to the process conditions disclosed in the patent applications for a particular polymorph. Three sets of experiments were prepared for the preparation of mentioned polymorphs: the first two sets were performed at a volume of 250 ml and the last set of experiments was increased to a volume of 7 l for the purpose of in-line monitoring of the Raman spectroscopy for polymorphic identification and FBRM (Focused Beam Reflectance Measurement) device that gives insight into the dynamics of the process. The granulometric characteristics of the product (shape, size and size distribution) were characterized by Scanning Electron Microscopy (SEM) and laser diffraction method to determine crystal size distribution. In the first two sets of experiments, X-Ray Diffraction (XRD) methods were confirmed by polymorphic forms A, B and C. At the amplification of XRD analysis as well as Raman spectroscopy only C omeprazole polymorphs were identified irrespective of which process the crystallization was carried out. The obtained results point to the importance of optimizing and parameterizing the industrial process of crystallization and the effect of increasing the process on the characteristics of the final product