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

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.

FORMULATION AND EVALUATION OF CAPTOPRIL BIOADHESIVE MICROSPHERES

In the present work, captopril microspheres using HPMCK100M, HPMCK15M and Carbopol 934 as copolymers were formulated by ionic cross linking technique (ionotropic gelation method) to deliver captopril via oral route. The technique was successfully employed to fabricate captopril microspheres and provides characteristic advantage over conventional microsphere method, which involves an “all-aqueous” system and thus avoids residual solvents in microspheres. Other methods utilize larger volume of organic solvents are costly and hazardous. Micromeritic studies revealed that the mean particle size was in the range of 512-903 μm. Increase in the polymer concentration led to increase in % yield, % drug entrapment effi ciency, particle size, % swelling and % mucoadhesion. The in vitro mucoadhesive study demonstrated that captopril microspheres using sodium alginate along with HPMCK100M as copolymer adhered to the mucus to a greater extent than the microspheres of captopril using albumin along with HPMCK15M and Carbopol 934 as copolymers.

ESTIMATION OF RESIDUAL SOLVENTS IN NETUPITANT API BY HEADSPACE GAS CHROMATOGRAPHY

Objective: Residual solvents are undesirable components present in Active Pharmaceutical Ingredients (API), excipients, or drug products. To meet the specific quality-based requirements, the presence of these solvents in pharmaceutical products should be monitored to ensure their safety. The main objective of this work is to develop a new method for the determination of residual solvents in netupitant API by an HS-GC method with an FID detector. Methods: An automated headspace GC method has been developed and validated for the estimation of the residual solvents-N-methyl pyrrolidine, xylene, toluene, and N, N Dimethylacetamide in netupitant API. The samples were dissolved in dimethyl sulfoxide and the equilibrium headspace gas was formed at 80 ᵒC, which was analyzed using a DB-624 column (30m*0.53 mm, 3.00 µm) with an injector and detector temperature set at 160 ᵒC and 230 ᵒC, respectively. The initial oven temperature was set at 60 ᵒC for 5 min and programmed at a rate of 10 ᵒC/min to the final temperature of 150 ᵒC, with a hold time of 5 min by maintaining the flow rate of 4.0 ml/min with a split ratio of 1:10, and total run time of 20 min. Nitrogen was used as carrier gas. The method developed was validated as per International Conference for Harmonization (ICH) guidelines for repeatability, linearity, range, ruggedness, detection limit, quantification limit, and recovery studies. Results: The linearity range selected was 50-350µg/ml and the correlation coefficient(γ2) values for all the solvents were found to be>0.99; recovery studies values were in a range of 90-110% and %RSD values were also found to be not more than 10 for the solvents. Conclusion: A novel, accurate, sensitive, and simple method was described for estimating residual solvents in Netupitant API by Headspace Gas Chromatography (HS-GC) coupled with a Flame Ionization Detector (FID). Excellent results have been observed for all the validated parameters with good peak resolution and lesser retention times.

Development and Validation of Head-space Gas Chromatographic Method in Tandem with Flame ionized detection for the determination of Residual solvents in Simeprevir API Synthesis

Residual solvent testing is an integral part of reference material certification. A gas chromatography/flame ionization detector/headspace method has been developed and validated to detect and quantitate commonly used residual solvents in our production processes: Methanol, Tetrahydrofuran, Toluene, Dichloromethane and Dichloroethane in Simeprevir API. A simple and selective HS-GC method is described for the determination & quantification of Residual Solvents in Simeprevir API. Chromatographic separation was achieved on USP G43 equivalent capillary column Thermo Scientific™ Trace GOLD™ TG-624 SilMS, 30m × 0.32mm × 1.8µm column (P/N 26059-3390) using nitrogen as carrier gas by using different temperature gradient of FID Detectors. Linearity was observed in the range 40-120% of standard concentrations for Methanol, Tetrahydrofuran, Toluene, Dichloromethane and Dichloroethane (r2>0.999) for the amount of solvent estimated by the proposed methods was in good agreement. The proposed methods were validated. The accuracy of the methods was assessed by recovery studies at three different levels. Recovery experiments indicated the absence of interference from commonly encountered diluent and API. The method was found to be precise as indicated by the repeatability analysis, showing %RSD less than 10 for Methanol, Tetrahydrofuran, Toluene, Dichloromethane and Dichloroethane. All statistical data proves validity of the methods and can be used for routine analysis of pharmaceutical active ingredients for estimation of Residual Solvents of Methanol, Tetrahydrofuran, Toluene, Dichloromethane and Dichloroethane in Simeprevir. Baseline separation of all five solvents and Simeprevir API is achieved within 20.5 minutes of analysis time. Method validation comprised the following parameters: limit of detection (LOD), limit of quantitation (LOQ), linearity and range, accuracy, precision (repeatability and intermediate precision), system suitability, specificity, and robustness. Linearity and LOQ (ppm) are listed for each solvent in manuscript. The present method was proven to be robust and accurate for quantitative analysis of residual solvent in neat materials.

Method of Validation for Residual Solvents in Bisoprolol Fumarate by GC Technique

Validation is important technique for detection, progress and estimation of drugs for pharmaceutical analysis. Aim of this article was to check the progress and validation of the method employed for the Residual Solvents in Bisoprolol Fumarate by Gas Chromatographic technique. The objective of this protocol is to validate a GC method of analysis for detection and Quantification of Residual Solvents Methanol, Acetone and Methylene dichloride in Bisoprolol Fumarate. In the pharmaceutical industry, validation policy is more important for documented of validation, types of validation and validation policy. The method was developed accurately and validation parameters are explained. Chromatographic condition was GC- 2014, gas chromatograph equipped with FID detector, column: 30 m x 0.32 mm ID x 1.8 µm DB - 624 capillary column or equivalent and column temperature was 45°C (hold 7 minutes) to 250°C @ 40°C/minutes, hold at 250°C for 3 minutes. The parameters such as Accuracy, Specificity, Precision, Linearity and Range, Limit of detection (LOD), Limit of quantitation (LOQ), ruggedness, robustness and system suitability testing with residual solvent such as Methanol, Acetone and methylene dichloride. All validation parameters are used in the routine and stability analysis.

A Review on – Estimation of Residual Solvents by Different Analytical Method

Residual solvents are the unwanted substances (solvents) used or created throughout the manufacture of a excipients, drug or pharmaceutical formulation and don't seem to be utterly removed by sensible ways within the final finished product. These solvents may be harmful in nature. Therefore, analysis of residual solvents becomes a necessary tool for the standard management of prescribed drugs. The appropriate limits for these substances are given in ICH. Solvents are widely used during the manufacturing, purification and processing of pharmaceutical substances. The residues of these solvents must be removed to the extent possible, as they do not have any therapeutic effect but can cause undesirable effects in the consumers. These solvent residues concentrationshould not exceed the limits prescribed in the ICH guidelines. This present review work is emphasized on various techniques (Loss on drying, Thermogravimetric analysis, Near- IR spectroscopy).