Fast real-time monitoring of entacapone crystallization and characterization of polymorphs via Raman spectroscopy, statistics and SWAXS

Abstract

Many active pharmaceutical ingredients (APIs) are small organic molecules that have different polymorphic forms (1). It is well known that the API's polymorphic form can affect its physico-chemical properties, such as density, melting point, solubility, stability, morphology and bioavailability (2). Thus, polymorphic screening is a critical part of preformulation studies. The search for possible polymorphic forms typically begins with crystallization of a drug substance from various solvents, including those frequently used during the final crystallization steps (3, 4). Since the API's physicochemical properties can have a dramatic impact on its therapeutic effect, it is crucial to detect the polymorphic form with the characteristics appropriate for the intended use. For this purpose, the parameters affecting the crystallization process should be controlled and optimized (5). Major limitations to improving the control of crystallization parameters Crystallization of the drug entacapone from binary solvent mixtures was monitored in situ using a Raman optical probe. The recorded Raman spectra and statistical analysis, which included the principal components method and indirect hard modeling made it possible to estimate the starting point of crystallization, to assess crystallization temperatures and to provide information on the polymorphic content of the mixture. It was established that crystallization temperatures were proportional to the volume content of the solvent in mixtures. The samples were also evaluated off-line via Raman spectroscopy and SWAXS. The collected data showed the presence of forms b and g in all solvent mixtures. In a toluene/methanol 30:70 mixture, in addition to forms b and g, at least one of the forms A, D or a was also indicated by SWAXS. The results have shown that the presence of a particular polymorph is strongly dependent on the nature and portion of the solvent in the binary solvent mixture.

Rapid Identification of Bioactive Carbohydrazide Reaction Products by an LC-DAD-SPE-NMR Approach

“…In chromatograms collected during the reaction course those peaks gradually increased while I and II decreased and vanished in the interval between 5 and 10 minutes thus indicating the end of the reaction. This finding is somewhat different from that previously observed by in-line vibrational spectroscopy and statistical methods [11] where the reaction endpoint in methanol was estimated to be around 30 minutes. According to LC area peak integrals condensation reactions gave 48 % of III and 52 % of IV which was similar to previous results.…”

“…The condensation of carbohydrazide (I) with salicylaldehyde (II) yielded a mixture of mono-(III) and bis(salicylidene)carbohydrazide (IV), as shown in Figure 1 [9,10]. We have recently reported that in-line Raman spectroscopy combined with multivariate data analysis could be applied for in-line monitoring of condensation reaction and for assessing the mixture content [11]. However, several drawbacks of this methodology, such as low sensitivity, complexity of the reaction mixture, and severe band overlapping, prevented precise identification of the compounds in the reaction mixture and determination of the reaction endpoints directly from the in-line spectra.…”

An Overview of Pharmaceutical Manufacturing for Solid Dosage Forms

“…30 is based on the properties of interest and associated techniques. This overview is by no means exhaustive, but covers many important aspects of pharmaceutical manufacturing, such as chemical composition (spectroscopic techniques such as infrared [202], near infrared (NIR) [86,137,203,204], Raman [86,[204][205][206][207], UV-Vis [208], ultrasound [209,210], laser induced fluorescence [211,212] and time of flight [213]), particle size and shape (laser diffraction [214][215][216], image analysis [138], focused beam reflectance measurement [217], spatial filter velocimetry [90,218]), crystallinity and polymorphism (small-and wide-angle X-ray scattering [123,219,220], NIR [221], Raman [221][222][223]) as well as physical properties (Terahertz [224,225], optical coherence tomography [224,226], focus variation [227], ultrasound [228]). …”

Process Simulation and Data Modeling in Solid Oral Drug Development and Manufacture

“…30 is based on the properties of interest and associated techniques. This overview is by no means exhaustive, but covers many important aspects of pharmaceutical manufacturing, such as chemical composition (spectroscopic techniques such as infrared [202], near infrared (NIR) [86,137,203,204], Raman [86,[204][205][206][207], UV-Vis [208], ultrasound [209,210], laser induced fluorescence [211,212] and time of flight [213]), particle size and shape (laser diffraction [214][215][216], image analysis [138], focused beam reflectance measurement [217], spatial filter velocimetry [90,218]), crystallinity and polymorphism (small-and wide-angle X-ray scattering [123,219,220], NIR [221], Raman [221][222][223]) as well as physical properties (Terahertz [224,225], optical coherence tomography [224,226], focus variation [227], ultrasound [228]). …”