Analysis of USP <7> Residual Solvents using the Agilent 797A Headspace Sampler with the Agilent 79B Gas Chromatograph Application Note Pharmaceuticals Authors Bart Tienpont, Frank David, and Pat Sandra Research Institute for Chromatography Kennedypark B- Kortrijk Belgium Roger L Firor Agilent Technologies, Inc. Centerville Rd Wilmington, DE 9 Abstract USP <7> residual solvents were analyzed by static headspace on the Agilent 797A Headspace Sampler combined with the Agilent 79B Gas Chromatograph. The previously described method performed on an Agilent 79A GC was directly transferred to the 79B GC. Excellent chromatographic performance was achieved at USP <7> specified limits and equivalent results were obtained. This test clearly indicated that methods can be transferred directly from an Agilent 79A GC to the 79B GC without modification.
Introduction Residual solvent analysis is a very important quality control procedure performed in the pharmaceutical industry. Sampling is typically performed by static headspace and analysis is done by GC/FID using a dedicated column. Often, a parallel column dual channel analysis by GC/FID or GC/FID/MSD is used. Previously, different configurations were described and tested in terms of repeatability, sensitivity and resolution []. The described dual channel GC/FID method was evaluated on the Agilent 79B GC. The original method was transferred to the GC, without modification. Repeatability, sensitivity, and resolution were all tested using residual solvent solutions in water of Class, Class A, and Class B compounds. Experimental Solutions Three stock solutions of residual solvents in DMSO were used: Residual Solvent Revised Method 7 Class (p/n 9-9), Residual Solvent Revised Method 7 Class A (p/n 9-9), Residual Solvent Revised Method 7 Class B (p/n 9-). These stock solutions were diluted in water to the USP specified limits according to the following scheme: Class solvents. ml stock solution vial plus 9 ml DMSO diluted to ml. ml from step diluted to ml with water ml from step diluted to ml with water. ml from step + ml water in a -ml headspace (HS) vial Table. Residual Solvents, Peak Number, USP Concentration Limits (ppm = mg/kg) and Repeatability (n = ) Obtained by HS-GC-FID on Column (VF) Identity USP limit (ppm) RSD (%) Class,-dichloroethene.,,-trichloroethane,.7 carbon tetrachloride.9 benzene.7,-dichloroethane. Class A methanol,. acetonitrile. dichloromethane. trans-,-dichloroethene,7. cis-,-dichloroethene,7. tetrahydrofuran 7. 7 cyclohexane,. methylcyclohexane,. 9,-dioxane. toluene 9.7 chlorobenzene. ethylbenzene,7., m-xylene, p-xylene,7. o-xylene,7. Class B hexane 9. nitromethane. chloroform.7,-dimethoxyethane. trichloroethene. pyridine. 7 -hexanone. tetralin.7 Class A solvents. ml stock solution vial, diluted to ml. ml from step + ml water in a -ml HS vial Class B solvents. ml stock solution vial, diluted to ml. ml step + ml water in a -ml HS vial The total sample volume was thus constant at ml in -ml headspace vials. Assuming a -mg drug substance sample in the headspace vial, the final residual solvent concentrations correspond to the USP concentration limits (Table ).
System Configuration Analyses were performed on an Agilent 797A Headspace Sampler coupled to an Agilent 79B GC. Figure shows the parallel dual column configuration. Experimental conditions Static headspace analysis was performed at C during minutes, according to the previously described method []. Table summarizes the experimental GC conditions. An Ultra Inert liner, p/n 9-9, with glass wool removed was installed in the split/spitless inlet. EPC Figure. Agilent 797A Headspace Sampler SSL. m µm id deactivated fused silica System configuration. Splitter un-purged HP-INNOWax (p/n 99N-) m µm id,. µm df VF-ms (p/n CP9) m µm id,. µm df FID back FID front Table. GC Conditions Conditions Column A Column B Carrier gas Agilent 79A GC m. mm id,. µm VF-ms (p/n CP9) m. mm id,. µm HP-INNOWax (p/n 99N-) Helium, kpa Injection Split/splitless C split ratio : Oven temperature C ( minutes) to C ( minutes) at C/min Detection (both channels) FID, C at Hz
Results and Discussion The chromatograms obtained for, respectively, Class, Class A, and Class B residual solvents are given in Figures. Peaks in the chromatograms can be identified by referring to Table. The obtained separations are very similar to those obtained previously on a 79A GC []. Elution order, resolution, and sensitivity are equivalent.. VF-ms. HP-INNOWax. 7 min,. 7 min Figure. Dual channel GC/FID profile of Class residual solvents at USP specification limits using an Agilent 797A Headspace Sampler and an Agilent 79B GC (peak identification: see Table ). VF-ms 7, HP-INNOWax 7 9, 9 min.9 min Figure. Dual channel GC/FID profile of Class A residual solvents at USP specification limits using an Agilent 797A Headspace Sampler and an Agilent 79B GC (peak identification: see Table ).
Note that Class solvents benzene and,-dichloroethene are baseline separated on the VF- column. The signal-to-noise (S/N) ratio for class solvents was for,-dichloroethene, for,,-trichloroethene, for carbon tetrachloride, for benzene, and 9 for,-dichloroethane; all clearly better than the required S/N >. These values were obtained with parallel column detection (: split between columns). Values using a single column would be x higher. The analysis was repeated six times, and the RSDs obtained on the VF- column are listed in Table. The average RSD was.%, which is excellent for static headspace sampling at these concentrations. This level of performance can be attributed to precise EPC controlled vial sampling, complete inert sample path, stable uniform thermal zones, and Capillary Flow Technology (CFT) devices. VF-ms 7 min HP-INNOWax 7 min Figure. Dual channel GC/FID profile of Class B residual solvents at USP specification limits using an Agilent 797A Headspace Sampler and an Agilent 79B GC (peak identification: see Table ).
Conclusions Methods developed for USP <7> residual solvent analysis on an Agilent 797A Headspace sampler combined with an Agilent 79A GC can be transferred to an Agilent 79B GC with preserved resolution, sensitivity, and repeatability. Excellent results were obtained at USP <7> specified limit concentrations for the three classes of residual solvents. References. R. L. Firor, Analysis of USP<7> residual solvents with improved repeatability using the Agilent 797A Headspace Sampler, Agilent Technologies application note 99-7EN, August.. USP -NF 7, General chapter USP <7>, Organic volatile impurities, US Pharmacopeia, Rockville, MD, /9 For More Information These data represent typical results. For more information on our products and services, visit our Web site at www.agilent.com/chem. www.agilent.com/chem Agilent shall not be liable for errors contained herein or for incidental or consequential damages in connection with the furnishing, performance, or use of this material. Information, descriptions, and specifications in this publication are subject to change without notice. Agilent Technologies, Inc., Printed in the USA January 9, 99-EN