ANALYSIS OF FORMULATED PRODUCTS

surfactants are determined as part of the complete analysis of a formulation such as a laundry detergent or cosmetic product, where the analyst has the goal of accounting for 

For this reason it is not generally possible to prepare a performance match for a competitive product on the basis of analysis alone. Also required is a skilled formulator who will use the analytical results as clues, rather than a recipe. For many purposes, such as estimating the manufacturing cost of a product or for determining whether patent infringement has occurred, an analysis accounting for considerably less than 100% is adequate. 

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This chapter provides a brief description of the strategies used to analyze formulations. The actual methodology for separation and analysis is described in the previous chapters. The reader is urged to also consult other works which give more detail on formulations and formulation analysis (1-5). The CTFA Compendium (6) and the publications of ASTM and the International Standards Organization are valuable sources of methods for determination of individual nonsurfactant components. 

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IR is a nondestructive technique suitable for the analysis of formulated products, and gives a considerable amount of information about the compounds present. Near-infrared (from 13 000 to 4000 cm ) and Fourier transform infrared (FTIR) (from 4000 to 400 cm ) spectroscopies are used. Qualitative analysis of the ethanol soluble fraction allows the identification of functional group types such as hydrotropes (xylenesulfonate and toluenesulfonate). In addition, zeolite, alkalis, polymers, and builders may be identified in the insoluble ethanol fraction. For quantitative analysis, method development is slow because a great number of calibration standards... 

A promising method for quantitation of anionic process surfactants is by cationic surfactant (e.g., Hyamine) titration monitored by a surfactant-sensitive electrode. The basic approach is described in references [76, 77, S9-92]. This technique has found application in the analysis of formulated products in the cosmetic [9J ] and pharmaceutical [90] industries and may... 

There are several approaches to the complete analysis of raw materials. The following range of methods gives the analyst a degree of choice. There are similar schemes based on the same principles, e.g. that of Battaglini et al. [24]. The analysis of formulated products probably calls for only the determination of the active and the chief impurity, i.e. the sulphonated carboxylate salt. 

Analysis of raw materials can be done in several ways, but analysis of formulated products is more difficult. 

BS 3762 Analysis of formulated products Part 1 Methods of sample division... 

Milwidsky, B. M., S. Holtzman, Soaps/syndets, Soap Chem. Spec., 1966,42(5), 83-86,154—158. Cullum, D. C., P. Platt, Analysis of formulated products, in M. R. Porter, ed.. Recent Developments in the Analysis of Surfactants, Elsevier, New York, 1991. 

From the FIA—MS overview spectrum, speculation that there can be more than just one structurally defined molecule type behind an observable signal i.e. the presence of isobaric compounds, cannot be excluded whenever one signal defined by the m/z-ratio is examined in FIA-MS spectra. Consequently, the information obtained by FIA-MS is quite limited whenever we deal with complex mixtures of environmental pollutants rather than the analysis of pure products or formulations with a known range of ingredients. LC separation is inevitable when mixtures of isomeric compounds should be identified with MS-MS. Therefore, in FIA-MS-MS special attention has to be paid to avoid the generation of mixed product ion spectra from isomeric parent compounds. This would block identification by library search and may lead to misinterpretations of product ion spectra because of the fragmentation behaviour observed. 

Kolbe noted also the formation of traces of methyl acetate and butyl valerate from electrolysis of acetate and valerate respectively. Careful analysis of reaction products by Petersen (1900) identified compounds which are today formulated as being derived from carbocations formed by loss of one electron from the alkyl radical [50]. Propanoic acid gives mostly ethene while butanoic acid and 2-methyl-propanoic acid give mostly propene. Acetate and long chain alkylcarboxylates give mostly the Kolbe type dimer hydrocarbon on electrolysis of their potassium salts in concentrated solution at a platinum electrode, using high current density and low temperatures [51]. 

It is in the development and support of formulated products that Raman spectroscopy probably has most to offer the life cycle of a pharmaceutically active molecule. Due to there being few limitations to sample presentation prior to analysis, Raman spectroscopy is particularly versatile and can be applied to both macro- and microsamples. 

Challenges for HPLC method development are for combination products where more than one active is present in the same formulation. Since degradation products are of big concern from a safety perspective, HPLC will continue to be utilized as a major separation technique during formulation development to develop the most safe and efficacious formulations to be used for human use. Many different types of bonded phases are currently available for routine HPLC analysis in addition, very selective and sensitive detection techniques can be integrated with HPLC to help an analytical chemist control the final quality of the drug product. Furthermore, the availability of this technique makes it the first and sometimes the only choice for the analysis of degradation products. 

The first part of a dossier contains basic information about the active substance and the applicant. Here are some examples name, structure, and route of synthesis of the substance must be described. The typical purity of the technical material and the identity isomers and impurities is determined by the analysis of five production batches to assess the reproducibility of the process and to help to identify fake products. In the next chapter the chemical and physical properties are described, determined according to official guidelines published by the OECD and other organizations. This applies to the active substance, all significant metabolites, and all formulated products. Some of the required studies are listed in Table 11.11. 

Change of product formulation involving excipients Major (DRA-3) Product full formula (in sealed envelope) Stability data to support new formulation Finished product specifications Certificate of analysis of finished product Product samples for both new and old formulation C2(c)... 

Is the method specific and stability indicating as shown by analysis of samples subjected to stressed stability studies (pH, light, heat, oxidation) Normally, specificity is determined through peak purity using ultraviolet (UV) diode array or liquid chromatography (LC)/mass spectrometry (MS) analysis. In methods for analysis of drug products, placebo formulations (and stressed placebos) must yield blank chromatographic baselines. The development... 

Additional information about the catalytic performance of the catalysts can be obtained from the analysis of the product distribution, which is affected by the metallic and acid functionalities. Tables 4 and 5 compare the product distributions obtained in the DBT and 4,6-DMDBT reactions with the NiMo/Al203, NiMo/HNaY and NiMo catalysts with 20% of HNaY in their formulation. In the case of DBT, zeolite incorporation into the catalyst changes the contributions of the direct desulfurization (DDS) pathway, which yields biphenyl-type compounds, and of the desulfurization through hydrogenation (HYD) pathway, which gives cyclohexylbenzene-type compounds. Also, the proportion of CHB in the reaction products and the liquid yield decrease with the number of accessible zeolite acid sites in the catalyst. This effect is due to the cracking of CHB on the zeolite acid sites. On the other hand, the formation of DCH is enhanced on the catalysts where Mo precursor phase is more polymerized (NiMo/HNaY-Al203(P) and NiMo/HNaY formulations). 

Chapter 10, on nuclear magnetic resonance spectroscopy was included because of the unique role that nuclear magnetic resonance spectroscopy has in the study of polymorphisms as well as in verification of compound identity and the structural confirmation of metabolic or decomposition products of drugs. Chapter 11, Vibrational Spectroscopy, reflects the invaluable contributions that those techniques such as infrared spectroscopy have made to the analysis of formulations, among other studies. 

British Standards BS 3762 and 6829 deal respectively with the analysis of formulated detergent products and raw materials. Some parts are identical with ISO Standards. Conversely some of the ISO Standards relating to surfactant analysis correspond with parts of these British Standards. The following list shows which Standards from either organisation correspond with those of the other. The words given here describe the subject matter but are only occasionally the official title of either Standard. 

Liu, J., Physical characterization of pharmaceutical formulations in frozen and freeze-dried solid states Techniques and applications in freeze-drying development. Pharm. Dev. Technol, 11 3-28 (2006). Whitfield, R.G, Near-infrared reflectance analysis of pharmaceutical products. Pharm. Manuf, 3 31 0 (1986). 

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