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Current Pharmaceutical Analysis

Editor-in-Chief

ISSN (Print): 1573-4129
ISSN (Online): 1875-676X

Research Article

Application of Gas Chromatography for the Analysis of Residual Solvents in Transdermal Drug Delivery Systems (TDS)

Author(s): Diaa Shakleya*, Sonal Mazumder, Naresh Pavurala, Sara Mattson and Patrick J. Faustino

Volume 18, Issue 7, 2022

Published on: 11 April, 2022

Page: [694 - 703] Pages: 10

DOI: 10.2174/1573412918666211217144635

Price: $65

Abstract

Background: Transdermal drug delivery systems (TDS) are widely used to deliver a number of different drug therapeutics. The design delivery can be impacted by excipients and, more broadly, organic solvents. Organic or residual solvents are routinely monitored due to safety concerns. However, there is little information on the mechanical properties and delivery performance of TDS.

Objective: The objective of this study was to develop and validate an efficient GC-Headspace method to determine the residual solvents (n-heptane, o-xylene, and ethyl acetate) in transdermal patches. The analytical method was applied to monitor residual solvents in TDS and evaluate the potential effect of the residual solvent levels on the TDS adhesion properties.

Methods: An Agilent GC 7890A was integrated with an Agilent headspace analyzer 7697A system and was used for method development, analytical method validation, and the testing phases of the study. For the analysis of residual solvents in TDS, 2cm x 3cm, a TDS sample was placed in a 20 mL Headspace vial containing 2 mL of a DMSO/water (1:1, v/v) solvent mixture, and an external standard (cyclohexane) was extracted by the headspace analyzer. The system suitability test was conducted according to USP <621>, and analytical method validation was conducted according to USP <1225> over 3 days for validation and was also performed during in-study sample analysis.

Results: The resolution between the solvents was acceptable (2.5, %RSD = 8.0). Intra- and inter- day accuracy and precision of all quality control standards as well as the spiked standards in the transdermal patches were found to be acceptable with RSD% ≤ 10% and accuracy ≥ 85%, respectively. Linearity was > 0.99 for all analytes.

Conclusion: The validated GC-Headspace method was successfully applied to a pilot study for in-house manufactured TDS patches to study the impact of residual solvent concentration on adhesion performance.

Keywords: Headspace-GC-FID, transdermal drug delivery systems, residual solvents, adhesion, product quality, n-heptane, oxylene, ethyl acetate.

Graphical Abstract
[1]
General Chapter on Organic volatile impurities. United States Pharmacopeia., 2009. Available from: https://www.pharmacopeia.cn/v29240/usp29nf24s0_c467.html
[3]
Bauer, M. Residual solvents in pharmaceutical substances. In: Handbook of Solvents; Wypych, G., Ed.; ChemTec: Toronto, 2001.
[4]
Doelker, C.W.E. Residual solvents in pharmaceutical products: acceptable limits, influences on physicochemical properties, analytical methods and documented values. Eur. J. Pharm. Biopharm., 1997, 43(3), 215-242.
[http://dx.doi.org/10.1016/S0939-6411(96)00037-9]
[5]
USFDA. Guidance for Industry. Residual Solvents in Drug Products Marketed in the United States. 2009. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/residual-solvents-drug-products-marketed-united-states
[6]
Tankiewicz, M.; Namiesnik, J.; Sawicki, W. Analytical procedures for quality control of pharmaceuticals in terms of residual solvents content: Challenges and recent developments. Trends Analyt. Chem., 2016, 80, 328-344.
[http://dx.doi.org/10.1016/j.trac.2015.09.008]
[7]
Newman, J. Solvent retention in organic coatings. Prog. Org. Coat., 1975, 3, 221-243.
[http://dx.doi.org/10.1016/0300-9440(75)80008-7]
[8]
Hays, D.R. Factors affecting solvent retention. Off. Dig, 1964, 36, 605-624.
[9]
Murdock, R.E. A method for measuring solvent release using radiotracers. Off. Dig., 1963, 35, 1084-1101.
[10]
Osawa, Z.; Aiba, M. Effect of residual solvent on the photodegradation of poly(vinyl chloride). Poly. Photochem., 1982, 2, 339-348.
[http://dx.doi.org/10.1016/0144-2880(82)90011-2]
[11]
Vachon, M.G.; Nairn, J.G. Physico-chemical evaluation of acetylsalicylic acid-Eudragit RS100 microspheres prepared using a solvent-partition method. J. Microencapsul., 1995, 12(3), 287-305.
[http://dx.doi.org/10.3109/02652049509010297] [PMID: 7650593]
[12]
Jelvehgari, M.; Atapour, F.; Nokhodchi, A. Micromeritics and release behaviours of cellulose acetate butyrate microspheres containing theophylline prepared by emulsion solvent evaporation and emulsion non-solvent addition method. Arch. Pharm. Res., 2009, 32(7), 1019-1028.
[http://dx.doi.org/10.1007/s12272-009-1707-y] [PMID: 19641883]
[13]
Aleksandra Groman, E.S.; Jatczak, M.; Lipiec-Abramska, E. Development and validation of gas chromatography methods for the control of volatile impurities in the pharmaceutical substance dutasteride. Acta Pol. Pharm., 2017, 74(5), 9.
[14]
Bao, Q.; Fu, K.; Ren, Q.; Zhong, Y.; Qian, D. Accuracy profiles for analyzing residual solvents in textiles by GC-MS. J. Chromatogr. Sci., 2017, 55(9), 882-890.
[http://dx.doi.org/10.1093/chromsci/bmx052] [PMID: 28605412]
[15]
Gangrade, M.G.; Gharat, H.P.; More, S.D.; Shinde, S.S.; Raval, V.K.; Sapre, J.V.; Alexander, R.T. A validated RP-HPLC method for the simultaneous determination of six high-boiling residual solvents in drug substances and its implementation in Apis. J. Pharm. Drug Deliv. Res., 2018, 6(6)
[16]
Kalchenko, O.I.; Golub, V.A.; Zavatskaja, I.V. HPLC and GLC determination of residual solvents in busulphan. J. Pharm. Biomed. Anal., 1995, 14(1-2), 107-111.
[http://dx.doi.org/10.1016/0731-7085(95)01617-1] [PMID: 8833972]
[17]
Soman, A.; Qiu, Y.; Chan Li, Q. HPLC-UV method development and validation for the determination of low level formaldehyde in a drug substance. J. Chromatogr. Sci., 2008, 46(6), 461-465.
[http://dx.doi.org/10.1093/chromsci/46.6.461] [PMID: 18647463]
[18]
Bursová, M. Hložek, T.; Čabala, R. Simultaneous determination of methanol, ethanol and formic acid in serum and urine by headspace GC-FID. J. Anal. Toxicol., 2015, 39(9), 741-745.
[http://dx.doi.org/10.1093/jat/bkv075] [PMID: 26178163]
[19]
Chun, H-J.; Poklis, J.L.; Poklis, A.; Wolf, C.E. Development and validation of a method for alcohol analysis in brain tissue by headspace gas chromatography with flame ionization detector. J. Anal. Toxicol., 2016, 40(8), 653-658.
[http://dx.doi.org/10.1093/jat/bkw075] [PMID: 27488829]
[20]
Kumar, N.; Egoville, J.C. Headspace gas chromatography method for the analysis of volatile impurities in a hormone replacement transdermal patch. J. Chromatogr. A, 1999, 859(1), 113-118.
[http://dx.doi.org/10.1016/S0021-9673(99)00825-0] [PMID: 10563422]
[21]
Jeong, E.J.; Lee, S.H.; Kim, B.T.; Lee, G.; Yun, S.S.; Lim, H.S.; Kim, Y.S. An analysis method for determining residual hexane in health functional food products using static headspace gas chromatography. Food Sci. Biotechnol., 2017, 26(2), 363-368.
[http://dx.doi.org/10.1007/s10068-017-0049-7] [PMID: 30263551]
[22]
Feng, X.Z.; Han, G.C.; Qin, J.; Yin, S.M.; Chen, Z. Determination of residual solvents in linezolid by static headspace GC. J. Chromatogr. Sci., 2016, 54(4), 487-491.
[http://dx.doi.org/10.1093/chromsci/bmv175] [PMID: 26657409]
[23]
Grodowska, K.; Parczewski, A. Analytical methods for residual solvents determination in pharmaceutical products. Acta Pol. Pharm., 2010, 67(1), 13-26.
[PMID: 20210075]
[24]
Tian, J.; Rustum, A. Development and validation of a fast static headspace GC method for determination of residual solvents in permethrin. J. Pharm. Biomed. Anal., 2016, 128, 408-415.
[http://dx.doi.org/10.1016/j.jpba.2016.06.020] [PMID: 27344630]
[25]
B’Hymer C. Residual solvent testing: A review of gas-chromatographic and alternative techniques. Pharm. Res., 2003, 20(3), 337-344.
[http://dx.doi.org/10.1023/A:1022693516409] [PMID: 12669951]
[26]
Górecki, T.; Martos, P.; Pawliszyn, J. Strategies for the analysis of polar solvents in liquid matrixes. Anal. Chem., 1998, 70(1), 19-27.
[http://dx.doi.org/10.1021/ac9703515] [PMID: 21644595]
[27]
Ettre, B.K.L.S. Static Headspace–Gas Chromatography: Theory and Practice; Wiley Online Library: Hoboken, New Jersey, 2006.
[28]
RESTEK. A Technical Guide for Static Headspace Analysis Using GC. 2000. Available from: https://d1lqgfmy9cwjff.cloudfront.net/csi/pdf/e/rk67.pdf
[29]
Klick, S.; Sköld, A. Validation of a generic analytical procedure for determination of residual solvents in drug substances. J. Pharm. Biomed. Anal., 2004, 36(2), 401-409.
[http://dx.doi.org/10.1016/j.jpba.2004.06.014] [PMID: 15496336]
[30]
Residual Solvents. Directorate for the Quality of Medicines of the Council of Europe, 4th ed; (Supplement 4.6), 2004.
[31]
Cheng, C.; Liu, S.; Mueller, B.J.; Yan, Z. A generic static headspace gas chromatography method for determination of residual solvents in drug substance. J. Chromatogr. A, 2010, 1217(41), 6413-6421.
[http://dx.doi.org/10.1016/j.chroma.2010.08.016] [PMID: 20801455]
[32]
Otero, R.; Carrera, G.; Dulsat, J.F.; Fábregas, J.L.; Claramunt, J. Static headspace gas chromatographic method for quantitative determination of residual solvents in pharmaceutical drug substances according to European pharmacopoeia requirements. J. Chromatogr. A, 2004, 1057(1-2), 193-201.
[http://dx.doi.org/10.1016/j.chroma.2004.09.023] [PMID: 15584239]
[33]
Gow, N.K.J.G. Residual solvent analysis by headspace gas chromatography. J. Chromatogr. A, 1994, 667(1-2), 235-240.
[http://dx.doi.org/10.1016/0021-9673(94)89072-2]
[34]
Tan, H.S.; Pfister, W.R. Pressure-sensitive adhesives for transdermal drug delivery systems. Pharm. Sci. Technol. Today, 1999, 2(2), 60-69.
[http://dx.doi.org/10.1016/S1461-5347(99)00119-4] [PMID: 10234208]
[35]
ICH Q2(R1) Validation of Analytical Procedures: Text and Methodology. 1996. Available from: https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q2_R1/Step4/Q2_R1__Guideline.pdf
[36]
USFDA. Reviewer Guidance: Validation of Chromatographic Methods.1994,
[37]
Guimbard, J.P.; Person, M.; Vergnaud, J.P. Determination of residual solvents in pharmaceutical products by gas chromatography coupled to a head-space injection system and using an external standard. J. Chromatogr. A, 1987, 403, 109-121.
[http://dx.doi.org/10.1016/S0021-9673(00)96345-3] [PMID: 3680405]
[38]
Haky, J.E.; Stickney, T.M. Automated gas chromatographic method for the determination of residual solvents in bulk pharmaceuticals. J. Chromatogr. A, 1985, 321(1), 137-144.
[http://dx.doi.org/10.1016/S0021-9673(01)90430-3] [PMID: 3988837]
[39]
Kersten, B.S. Drug matrix effect on the determination of residual solvents in bulk pharmaceuticals by wide-bore capillary gas chromatography. J. Chromatogr. Sci., 1992, 30(4), 115-119.
[http://dx.doi.org/10.1093/chromsci/30.4.115] [PMID: 1328274]
[40]
U.S. Food and drug administration. center for drug evaluation and research: Assessing adhesion with transdermal delivery systems and topical patches for ANDAs draft guidance for industry. 2018. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/assessing-adhesion-transdermal-delivery-systems-and-topical-patches-andas-draft-guidance-industry
[41]
European Medicines Agency: Guideline on quality of transdermal patches. 2015. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-quality-transdermal-patches_en.pdf
[42]
Cilurzo, F.; Gennari, C.G.; Minghetti, P. Adhesive properties: A critical issue in transdermal patch development. Expert Opin. Drug Deliv., 2012, 9(1), 33-45.
[http://dx.doi.org/10.1517/17425247.2012.637107] [PMID: 22171789]

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