ANALYTICAL METHODS FOR RESIDUAL SOLVENTS INTRODUCTION:
Organic solvents are routinely applied during synthesis of drug substances, excipients, or during drug product formulation. They are not desirable in the final product, mainly because of their toxicity, their influence on the quality of crystals of the drug substance and their odor or taste, which can be unpleasant for patients. To remove them, various manufacturing processes or techniques (usually under increased temperature or/and decreased pressure) are in use. Even after such processes, some solvents still remain, yet in small quantities. These small quantities of organic solvents are commonly known as organic volatile impurities (OVIs) or residual solvents (RS). In the early 80s, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human use (ICH) was established. Then, in late 80is, RS were classified as impurities. Categories of residual solvents were presented in the preceding paper. The ICH Harmonized Guidelines set up by the EU, Japan and USA for the registration of pharmaceutical products require, under ICH Topic Q3C (published in December 1997), for testing to be performed for residual solvents when production or purification processes are known to result in the presence of such solvents. These guidelines set criteria for analytical methods used to identify and quantify these residual solvents as well provide acceptable concentration limits. USP has finally adopted the ICH Q3C guidelines set and has revised its general methods to reflect it. The new general chapter states what ICH Q3C contains, and in addition describes analytical methods for performing RS testing. Limits and different methods for determination of RS have been finally integrated in USP (1).
Methods accepted by pharmacopoeias and ICH Guidelines
* The first analytical method for RS, which was published in pharmacopoeias, was a loss of weight. This method could be carried out at normal pressure and/or under vacuum. The loss of weight is a simple and not demanding method. * But apart from that it has many disadvantages, including lack of specificity, high limit of detection (about 0.1%), and also a relatively large amount of sample needed to perform the tests (about 1 n 2 g). Moreover, atmospheric humidity can significantly modify the results obtained by the loss of weight method. * Nowadays, for this kind of determination, more sophisticated techniques like thermo gravimetric analysis (TGA), differential thermal analysis (DTA) or differential scanning calorimetry (DSC), which will be described more precisely in later paragraphs, can be used * Gas chromatography (GC), due to the volatility of organic solvents and the substantial separating capability of capillary columns, has dominated analytical methods for RS determinations. It is no wonder, that pharmacopoeias also adopted this technique for RS determination. The methods and their usage are described in general chapters and in individual monographs. * Current official methods for RS determination are described in USP XXXI in <467> chapter Organic Volatile Impurities. Under Identification, control, and quantification of residual solvents three procedures (A, B, C) for water-soluble and water-insoluble articles, are available. * Procedures A and B are useful to identify and quantify residual solvents, when the information regarding which solvents are likely to be present in the material is not available. * In cases when we have information about residues of solvents that may be expected in the tested material, only procedure C is needed for quantification of the amount of RS. All these methods exploit gas chromatography with capillary or wide-bore columns, static headspace injector, and flame ionization detector (FID). * These procedures differ among themselves in column type (dimensions and film-coatings)...
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