Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
1999-05-26
2001-05-15
Kumar, Shailendra (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C424S009454
Reexamination Certificate
active
06232499
ABSTRACT:
This invention relates to improvements in and relating to the manufacture of iodinated organic X-ray contrast agents.
For many years, the X-ray contrast media market has been dominated by the inorganic barium compounds used for imaging the gastrointestinal tract and the parenterally-administered organic iodinated compounds used for imaging elsewhere, in particular the circulatory system. These iodinated compounds, such as iohexol, iopentol, iodixanol, ioversol, iopamidol, ioxaglate, metrizoate, metrizamide, etc., are manufactured and sold as pharmaceuticals and as with the commercial manufacture of any pharmaceutical compound it is important to optimize their efficiency of manufacture (eg. to maximize yield and purity while minimizing demand on equipment, materials and time).
As pharmaceuticals however, the manufacture of iodinated X-ray contrast agents is dominated by the requirement for product purity and accordingly most process steps are monitored using the “gold standard” of HPLC which gives a clear and unmistakeable indication of the presence and likely identity of by-products and residual reagents in any reaction mixture.
HPLC however is a relatively slow technique taking perhaps several hours from sampling to completion of data analysis and offers little freedom to the process operators for real-time feedback control of process performance.
The present inventors have now realised that more rapid, and indeed on-line monitoring, of the processes for the production of iodinated X-ray contrast agents can surprisingly be achieved using vibrational (eg. near infrared (NIR), infrared or Raman) spectroscopy. Such an on-line monitoring system allows a more rapid response in process control, eg. in terms of changing process conditions such as temperature, pressure and pH, controlling addition of reagents, or terminating reactions at the optimal point. That such spectroscopic techniques can be used for this purpose is doubly surprising. Firstly, it is surprising that a spectrum of a complex reaction mixture can be used as such to reliably predict the amount of single species, without first requiring the use of separation techniques such as chromatography, even when product purity is of paramount concern such as is the case with drug substances. Secondly, vibrational spectrometry has for many years been viewed as an academic tool, with little or no relevance for process monitoring and complex reaction mixtures. Contrary to what was believed, it is now surprisingly found that vibrational spectroscopic techniques (eg. infrared and NIR spectrometry) are applicable even to reaction mixtures with high aqueous contents. With Raman spectroscopy, high water contents of the solvent are not problematic. Raman spectrometry, moreover, is particularly sensitive to detection of molecular species with large numbers of polarisable electrons, such as iodinated X-ray contrast agents.
NIR spectroscopy has previously been used for monitoring of hydrocarbons (see for example WO 91/15762, U.S. Pat. No. 4,963,745, DD-272129 and WO 89/06244) but has not previously been suggested as being suitable for monitoring production of contrast agents, especially X-ray and MRI contrast agents.
Thus viewed from one aspect, the present invention provides a process for the production of an organic iodinated X-ray contrast agent, characterized in that process control comprises vibrational (eg. infrared, Raman or preferably near-infrared) spectroscopic monitoring of the reaction mixture in at least one of the process steps, preferably one of the final reaction steps.
Monitoring using vibrational spectroscopic techniques according to the invention will typically involve deriving characteristic data values from the detected spectra, comparison of such characteristic values with calibration data and modification of process parameters based on the outcome of the comparison. All these steps may, and preferably will, be automated with the process of the invention being operated under computer control.
The manufacturing of contrast agents, eg. organic iodinated X-ray contrast agents, includes production of the chemical drug substance (the “primary production”), followed by formulation to the drug product (the “secondary production”). The drug substance is usually made and purified in a multi-step chemical synthesis and the monitoring according to the invention may take place in one, some or all of these multiple steps, and particularly conveniently comprises monitoring of the reactor contents in at least one, and preferably two to six, of the final reaction steps. For the purposes of the present invention a reaction step is defined as a process which involves converting one isolatable and purifiable compound into another or the transformation of a compound from one form to another (eg. a precipitation or crystallization or a phase change or the formation of an amorphous form of a product) and/or an essentially mechanical step such as the cleaning of equipment. Such compounds will either be reagents (starting materials not manufactured by the process operator), intermediates, or the final drug substance.
The vibrational spectra of crystalline iodinated organic X-ray contrast agents are usually sufficiently different from those of the corresponding amorphous materials or indeed from those of the same agents in different crystalline forms as to allow unambiguous identification of the crystalline form being monitored. Raman spectra show the same level of detail as infrared spectra with respect to band shifts and splittings caused by different solid (polymorphic) forms of a substance, but Raman spectrometers are more conveniently coupled on-line, eg. to a reaction vessel in which an iodinated X-ray contrast agent is precipitated from a solution. The grain size of the resulting solid will also affect the appearance of the infrared, NIR and Raman spectra, so that other physical characteristics of the solid could also be inferred from the spectra.
In one embodiment, the present invention therefore involves a process for the production of an iodinated X-ray contrast agent, involving an on-line quantitative monitoring of physical characteristics (eg. crystal size, crystal type, etc.) of the desired product. This monitoring may be done on-line during precipitation of the solid substance, by multivariate calibration and/or classification and Raman spectrometry coupled to the reaction vessel by means of optical fibres and a suitable optical window through which the exciting laser light is transmitted and the resulting Raman scattering is collected and transmitted back to the spectrometer. Alternatively, commercially available infrared waveguides and optical windows may be used to connect an infrared (FT-IR) spectrometer to the reaction vessel, or a NIR spectrometer may be connected using optical fibres, and the spectral data may be collected and the physical characteristics of the precipitate may be predicted from a suitable multivariate calibration and/or classification model, eg. based on reference spectra of pure polymorphs or mixtures thereof.
In the process of the invention, vibrational spectroscopic data (eg. NIR spectroscopic data) are collected for the reaction mixture, either by in-situ measurement, on-line sampling (eg. drawing off a sample through a line delivering the sample to the spectroscopic apparatus) or off-line sampling (eg. drawing off of a discrete sample and placing some or all of that sample in the spectroscopic apparatus). The sample monitored may thus be in or taken from a reaction vessel or a duct connecting reaction vessels. All of these data collection steps may be effected automatically, eg. under computer control; however of these, in situ measurement and on-line sampling are preferred since the delay before spectroscopic measurement can be minimized.
The spectroscopic data generated is conveniently subject to an automated calculation procedure, eg. based on a previously established multivariate calibration, allowing almost instantaneous feedback to the process control system (which will conveniently be compu
Aabye Arne
Bjørsvik Hans René
Brekke Geir
Malthe-Sørenssen Dick
Schelver Hyni Anne Cathrine
Bacon & Thomas
Kumar Shailendra
Nycomed Imaging AS
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