Category: Formulation and Quality
Purpose: Transdermal systems (TDS) patches are used to deliver drugs through the skin for either a local or systemic therapeutic effect. The permitted amounts of residual organic solvent in the TDS patch are specified in the applicable ICH Q3C guideline (International Conference on Harmonization, 2011). Class 3 solvents are limited generally to 5000 ppm or 0.5% (w/w), whereas Class 2 solvents have individual ppm limits. Residual solvent in TDS is commonly tested in-process and for the finished product. The objective of present work is to implement a novel headspace GC/FID method to efficiently evaluate the concentration of residual solvent in the marketed transdermal patches.
Methods: An integrated Agilent GC 7890A-headspace analyzer 7697A system was employed for the method development, validation and implementation phases of the study. The amount of residual solvent (ethyl acetate, n-heptane, and o-xylene) in the TDS commercial patches were analyzed using the newly developed GC-headspace method. For the analysis of residual solvents in TDS, 2cm x 3cm TDS sample was placed in a 20 mL GC vial containing 2 mL of a DMSO/water (1:1, v/v) solvent mixture and the external standard (cyclohexane) were extracted by the headspace analyzer. Three different over the counter (OTC) transdermal patches (with inter and intra variation data, N=3) as well as five prescribed transdermal patches were tested for the residual solvents content.
Results: Selected OTC transdermal patches tested for residual solvents were found to contain higher amount of o-xylene with average intra-concentration ranges 6223-9566 ppm (≤77.36, %CV), and inter-concentration ranges, 7721-8024 ppm (≤47.3, %CV). whereas for the n-heptane residual solvent content, the average intra-concentration ranges were 455-3395 ppm (≤59.60, %CV), and inter-concentration ranges, 1415-2095 (≤19.70, %CV). However, the residual solvents variation for the five prescribed TDS were found to be ≤ 15 %CV where the average variation in concentration does not exceed 100 ppm.
Conclusion: TDS prescribed and OTC patches with n-heptane and o-xylene contents were successfully tested using the novel headspace GC method. The evaluation of residual solvent in the OTC TDS patches showed a higher amount of n-heptane and o-xylene with large inter and intra solvent variation, ≤77 %CV between TDS products. In summary, prescribed TDS patches had lower residual solvent levels for n-heptane and o-xylene (≤5000 ppm, ICH Q3C recommendation for class 3 solvents) and lower variation between products.
Sonal Mazumder– Research Scientist, US Food and Drug Administration, Silver Spring, Maryland
Naresh Pavurala– Research Scientist, US Food and Drug Administration, Silver Spring, Maryland
Sara Mattson– Silver Spring, Maryland
Patrick Faustino– Silver Spring, Maryland