Article pubs.acs.org/OPRD
Using PAT To Understand, Control, and Rapidly Scale Up the Production of a Hydrogenation Reaction and Isolation of Pharmaceutical Intermediate Peter Hamilton,*,‡ Mahesh Jayantilal Sanganee,† Jonathan P. Graham,† Thoralf Hartwig,§ Alan Ironmonger,† Catherine Priestley,† Lesley A. Senior,‡ Duncan R. Thompson,‡ and Michael R. Webb† †
Global API Chemistry, GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, U.K. Process Analytical Technology Group, Analytical Sciences, GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, U.K. § Particle Sciences, Devices and Engineering, GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, U.K. ‡
S Supporting Information *
ABSTRACT: The development of a hydrogenation process and subsequent isolation for an intermediate in the manufacture of an active pharmaceutical ingredient is described. In-line process analytical technology (PAT) approaches were applied to gain process understanding and control. First, a calibration-free, qualitative, scale-independent approach using in situ mid-infrared (MIR) spectrometry to determine the end point of a hydrogenation reaction in real time is described. A curve-fitting algorithm was developed using MATLAB software to allow the reaction rate to be calculated at any given time during the reaction on the basis of the consumption of an intermediate species. The algorithm, coupled with understanding of the process, allowed the end point to be correctly identified in triplicate during scale-up of the process from 0.2 to 20 L scale. Second, a quantitative partial least-squares (PLS) regression model was developed using near-infrared (NIR) spectrometry to determine the solvent composition during the subsequent constant-volume distillation process prior to the crystallization of the hydrogenated product. Here the application of in-line NIR spectroscopy allowed the correct crystallization seed point to be determined, enhancing the control of quality and manufacturability.
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INTRODUCTION
group. Reduction of the aromatic ring system can also occur, leading to an over-reduced impurity. During a previous API manufacturing campaign, frequent samples for off-line HPLC analysis were required in order to ensure that both the intermediate and over-reduced impurities were within the required specifications at the reaction end point. This approach was not suitable for transfer to commercial manufacture because of the high time and resource requirements of multiple off-line analyses. A variable reaction end point also meant that a fixed reaction time approach was not suitable. In this article, the optimisation of the process and development of in situ MIR spectrometry as a control based on the consumption of the intermediate will be discussed. Isolation of the product from the reaction mixture was also challenging because of the presence of chemically unstable polymorphic forms. Previous isolations from alcohol/antisolvent mixed solvent systems led to noncrystalline and nonstable solid forms with inconsistent purging of impurities. In order to manufacture material of consistent quality and enable facile commercial manufacture, a controlled crystallization giving consistent impurity purging and stable product was required. To enable this, a solvent exchange distillation process was employed, and the utilisation of near-infrared
Since the FDA guidance for process analytical technology (PAT) was issued in 2004, the pharmaceutical industry has seen an increase in the use of in situ technologies for reaction monitoring and control for most commonly utilised manufacturing operations.1−6 The use of PAT can significantly reduce both manufacturing risks, such as yield loss, unstable form production, or poor filtration and drying, and quality risks, such as the formation of impurities at unsafe levels. In-line spectroscopy has been used extensively for monitoring of chemical reactions and crystallization processes from the laboratory through at least pilot-plant scale.7−9 For hydrogenation reactions, the focus of recent examples in the literature has been on the use of mid-infrared (MIR) spectroscopy to gain a fundamental understanding of the process, to understand the effects of changing process conditions, or to determine the reaction kinetics.10−13 However, there has been less focus on process control or real-time determination of the reaction end point. For distillation and crystallization processes, recent examples have included quantitative models using a range of spectroscopies to control solvent composition.14,15 A key step in the synthesis of an active pharmaceutical ingredient (API) under clinical development at GSK is a hydrogenation reaction using a Pd/C catalyst in methanol to remove both the O- and N-benzyl groups from a synthetic intermediate (Figure 1). The reaction predominately proceeds to product via an N-benzyl intermediate (hereafter called the intermediate) due to the rapid hydrogenolysis of the O-benzyl © XXXX American Chemical Society
Special Issue: Process Analytical Technologies (PAT) 14 Received: September 3, 2014
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dx.doi.org/10.1021/op500285x | Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
Article
Figure 1. Schematic representation of synthetic steps involved in the hydrogenation process (Bn denotes benzyl).
distillation was performed to reduce the methanol content to
