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Static headspace gas chromatographic method for the determination of low and high boiling residual solvents in Betamethasone valerate

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Abstract

Currently, there are no analytical methods available in the literature that can simultaneously separate and quantitate residual levels of acetone, methylene chloride, n-butyl ether and dimethylsulfoxide in Betamethasone valerate active pharmaceutical ingredient (API). This paper describes the development and validation of a simple, efficient, accurate and robust static headspace gas chromatography method for the determination of high and low boiling residual solvents, namely acetone, methylene chloride, n-butyl ether and dimethylsulfoxide, in Betamethasone valerate API. This method has been demonstrated to be accurate, linear, precise, reproducible, specific and robust for its intended purpose. Quantitation limits (QL) for acetone, methylene chloride and n-butyl ether are 20 ppm (20 μg/g of API) and 50 ppm (50 μg/g of API) for dimethylsulfoxide. Several other APIs (Loratadine and a few other corticosteroid compounds) were analyzed using the conditions of this method to evaluate and assess the versatility of this method for the purpose of residual solvents analysis for a wide range of APIs. The results of this evaluation strongly indicates that this method can be readily used (as-is or with minor modifications) to determine both low and high boiling residual solvents present in a wide range of APIs.

Introduction

Residual solvents (RS) in active pharmaceutical ingredients (API) encompass volatile organic compounds that are either used or produced during the manufacturing of an API. Depending on the type/class of solvent, high levels of RS in APIs can pose a potential safety risk to patients’ health due to their toxicity and other undesirable adverse effects. It is a mandatory requirement by various health authorities in the world to accurately determine the levels of RS that are present in APIs. The presence of RS in an API could also play a critical role in the physiochemical properties (i.e., physical forms) and or physical appearance and other characteristics (e.g., color, odor, etc.) of the bulk API lots [1], [2], [3]. Hence, appropriate attempts are always taken in the manufacturing of APIs (such as drying) to eliminate and or minimize the presence of RS in the bulk lots of APIs. However, depending on the characteristics of the API, RS, and drying conditions/parameters of the API, various levels of RS can be retained in the final bulk lots of APIs.

According to the guidelines of International Conference on Harmonization (ICH), RS are divided into four different classes from most toxic solvents to solvents with insignificant toxicological effect on human health [4], [5]. Excellent sensitivity and high selectivity of gas chromatography (GC) for volatile compounds makes it one of the most practical and popular techniques to determine RS in bulk APIs. In last decade, sampling techniques using static headspace gas chromatography (SHGC) gained preference and popularity over the direct injection GC because of various complications and disadvantages caused by the direct injection of the API into the GC system [6]. SHGC methods minimizes any potential interference caused by non-volatile substances (or by the degradation/decomposition products of the non-volatile components) as a result of direct injection into the GC system. Further, the direct injection method requires relatively high sample concentration, and this often leads to poor chromatography (for capillary columns) and limited injections of samples per sequence of sample analysis. Consequently, SHGC with FID detection has been widely used for the analysis of organic volatile ingredients present in the bulk lots of API and drug products [7], [8], [9], [10], [11], [12], [13].

Betamethasone valerate (BV) is a steroid with anti-inflammatory properties and is used to manufacture dermatological drug products for topical applications. Both low boiling (acetone and methylene chloride) and high boiling (n-butyl ether and dimethylsulfoxide (DMSO)) solvents are used in the final steps of BV synthesis. Though compendial methods such as the United States Pharmacopeia (USP), European Pharmacopeia (Ph. Eur.), etc., list procedures for the analysis of different types of organic solvents, this list does not cover all potential solvents such as n-butyl ether, one of the solvents used in the manufacturing of BV. The general procedure of Ph. Eur. and USP for RS determination in pharmaceutical products includes analysis of many solvents and hence a longer GC cycle time (∼70 min) [14], [15]. However since only a handful of the solvents were used in the manufacturing of BV our objective was to develop a simple, robust and efficient SHGC method that can accurately quantitate all the four RS present in commercial bulk API lots of BV.

In this paper, we describe the development and validation of an efficient, accurate, sensitive and rugged SHGC method for quantitation of RS present in commercial bulk API lots of BV. In addition, we also presented validation data on two alternative columns and application of this method for the determination of RS in other APIs (namely Loratadine and other corticosteroid APIs).

Section snippets

Materials

Betamethasone valerate, Betamethasone Sodium Phosphate, Mometasone Furoate Monohydrate, and Loratadine API was provided by ACDS-Supply Analytical Sciences group of Merck & Co., Inc. (Union, New Jersey, USA). Primary vendor for 1,3-dimethyl-2-imidazolidinone (DMI) and n-butyl ether was Acros (NJ, USA), acetone and methylene chloride was Fisher Chemicals (Fairlawn, NJ, USA) and dimethylsulfoxide (DMSO) was Burdick and Jackson (Muskegon, MI, USA). All solvents were either ≥98% pure or HPLC/GC

Analytical method development

Critical elements of a new SHGC method development are: (i) identifying an appropriate diluent which would completely dissolve the API; (ii) determining suitable headspace parameters (i.e., headspace temperature, vial equilibration time, vial pressurization), GC parameters (i.e., inlet split ratio, inlet temperature) and GC temperature programming to improve the sensitivity of the method; (iii) determining the detection limit (DL) and QL levels based on the sensitivity of the method.

Conclusions

The SHGC method developed for the identification and quantitation of residual acetone, methylene chloride, n-butyl ether and DMSO in the samples of BV API has been successfully validated. This is the first reported headspace GC method for n-butyl ether. This method has been shown to have a high sensitivity since it has a low DL and QL of 4 ppm and 20 ppm for acetone, methylene chloride, and n-butyl ether. The DL and QL for DMSO are 10 ppm and 50 ppm, respectively. This method has also been

Acknowledgements

The authors would like to thank all the analytical scientists in Merck & Co., Inc., ACDS-Supply Analytical Sciences group for their support of this study.

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