Pharmaceutical Mixtures

Many pharmaceuticals need more investigation about their potential long-term eco-toxicological effects. There is also a general lack of chronic toxicity data on pharmaceuticals, in particular in fish. Furthermore, the potential of combined effects of pharmaceutical mixtures should be addressed. 

Fent, K., Escher, C. and Caminada, D. (2006) Estrogenic activity of pharmaceuticals and pharmaceutical mixtures in a yeast reporter gene system. Reprod. Toxicol., 22 (2), 175—185. 

HPLC-UV-NMR can now be considered to be a routine analytical technique for pharmaceutical mixture analysis and for many studies in the biomedical field. HPLC-UV-NMR-MS is becoming more routine with a considerable number of systems now installed worldwide, but the chromatographic solvent systems are limited to those compatible with both NMR spectroscopy and mass spectrometry. The increased use of HPLC-UV-IR-NMR-MS is possible, but it is unlikely to become widespread, and the solvent problems are more complex. The future holds the promise of new technical advances to improve efficiency, and to enhance routine operation. These approaches include the use of small-scale separations, such as capillary electrochromatography, greater automation, and higher sensitivity and lower NMR detection limits through the use of NMR detectors cooled to cryogenic temperatures. 

Rapaport and Solyanik (168) have developed a rapid method of refractometric determination of 23 mixtures containing anesthesin, barbamyl, bromcamphor, bro-misoval, camphor, antipyrine, amidopyrine, acetalsali-cylic acid, barbital, codeine, salol, terpin hydrate, hexamethylenetetramine, and phenobarbital. The method described is suitable for analysis of pharmaceutical mixtures containing compounds which are insoluble in water and soluble in ethanol. A mixture of 2 pharmaceuticals (0.1 g) is dissolved in 1 ml. ethanol and np of this solution is determined. One component is... 

Salicylamide had been estimated spectrophotometrically as a single component, in complex pharmaceutical mixture and analgesic tablets by several procedures among them are the following ... 

Used for the precolumn preparation of fluorescent derivatives of aldehydes and ketones reagent suggested to be especially useful because of its application on the microlevel, for the analysis and identification of carbonyl compounds in smog, polluted air, and biochemical and pharmaceutical mixtures reagent does not appear to be useful for analysis of sugars derivatives are fluorescent in the UV as solids and in solution References 21, 22... 

Abatzoglou N. 2005. Prediction of segregation tendency occurrence in dry particulate pharmaceutical mixtures development of a mathematical tool adapted for granular system application. Pharm. Dev. Technol. 1 59-70. 

Drops Drops are pharmaceutical mixtures meant to be given in small amounts. Before the twentieth century, the term applied to solutions used in small quantities expressed in drops. These were commonly... 

Simultaneous quantitative analyses, of complex pharmaceutical mixtures, has been accomplished by the Rietveld methodJ Using lithium fluoride as an internal standard, mixtures consisting of anhydrous p-carbamazepine, anhydrous a-carbamazepine, and carbamazepine dihydrate were subjected to quantitative analyses (Table 2). When the analyte concentration was high (>20%), the method was accurate, with a relative error < 5%. However, when the analyte concentration was low (<5%), the method lacked accuracy. 

Rietveld, H.M. Profile refinement method for nuclear and magnetic structures. J. Appl. Crystallogr. 1969, 2, 65-71. Iyengar, S.S. Phadnis, N.V. Suryanarayanan, R. Quantitative analyses of complex pharmaceutical mixtures by the rietveld method. Powder Diffr. In press. 

Williams [17] has commented on the standard deviation as a measure of quality for a mixture of dry powders. The technique offers certain disadvantages, according to Williams. First, a pharmaceutical mixture is a complex assembly of particles and it may not be reasonable to assume that it can be adequately described by a single statistic like standard deviation. 

A pharmaceutical mixture contains two drugs, sulfanilamide and sulfathiazole. When the UV spectrum of the mixture was obtained, it was found that the two spectra overlapped as shown below in Figure 7.26. Pure samples of each drug were available and the spectrum for each drug was obtained under identical conditions. Using the data tabulated below, calculate the concentrations of each drug in the mixture. 

There are some pharmaceutical mixtures where all components except one vary within quite narrow limits. The remaining component, normally a diluent or a solvent is considered as being a "filler", a "slack variable", or "q.s." This situation has already been treated using factorial designs in chapter 3 and using the central composite design in chapter 5. The variables (except for the filler) can be varied independently and, therefore, the problem may be treated by the methods appropriate to independent variables. 

We now consider the other extreme case, where there is no restriction on the proportion of each component, each being allowed to vary between 0 and 100%. This does not on the face of it appear very useful for pharmaceutical mixtures, but we will also see that mixtures where only lower limits are imposed on the proportions of each component have an identically shaped design space and can be treated using the same experimental designs. 

Preparative TLC is an ideal quantitative technique for radioactive and toxic substances and for feasibility studies of reactions of expensive pharmaceutical mixtures. A recent innovation has been the introduction of taper plates (Analtech) for use in preparative TLC work. The dimensions and features of the taper plate are illustrated in Figure 3.14. Sample concentration prior to separation occurs in the pre-adsorbent zone. The tapered adsorbent layer causes low R bands to separate further than on a preparative plate of constant thickness. A more uniform mobile phase flow pattern and reduced vertical band spreading, further enhance the performance. 

The following example for the optimization of mobile-phase composition by gradient runs refers to a separation of the same pharmaceutical mixture as specified in Figure 3.54. LiChrospher RP-18 (Lc = 250 dc = 4mm) is used as adsorbent and the mobile phase is a mixture of acetonitrile and water. Figure 3.57 shows the initial... 

Traditional applications for ion mobility spectrometry (IMS) have primarily revolved around security and safety because of the rapid response time of the instrument coupled with its selectivity and sensitivity. Its speed, sensitivity, and selectivity, however, open opportunities for expansion into other areas of analysis. Pharmaceuticals offer a particularly promising target area for application of IMS because, unlike environmental and biological samples, pharmaceutical mixtures are usually well defined and not too complex. In addition, many pharmaceuticals have basic sites on the molecules that produce high proton affinities thus, they respond well to the ion-molecule ionization sources used in positive-mode IMS. Analytical methods currently used in the pharmaceutical industry revolve around some type of chromatography, either liquid or gas, that is usually slow and expensive. For routine, repetitive, and rapid analyses of pharmaceutical samples, IMS offers a unique and efficient alternative to chromatography. 

E. W. Ciurczak, Identification and Quality Assessment of Incoming Raw Materials and Pharmaceutical Mixtures, presented at AAPS National Meeting, Las Vegas, November, 1990. 

Drennen and Fodder [116] published a paper in 1991 comparing the performance of the improved quantile-BEAST algorithm with that of the Mahalanobis distance in the qualitative analysis of carbamazepine tablets. While the Mahalanobis distance calculation assumes that spectral variations associated with both the calibration and test set are random, in complex pharmaceutical mixtures this may not be the case. The bootstrap algorithm, on the other hand, is a nonparametric test which can be used with nearly any spectral data distribution. 

Chemometric approaches have been used to improve the reliability of quantitation for pharmaceutical mixtures. Chlorpropamide is a polymorphic antidiabetic drug. Thirteen binary mixtures of forms A and B were prepared and statistically analyzed by factor analysis programming [34]. Subsequent predictions of compositions were correlated with theoretical amounts of the two polymorphs and showed the value of the factor analysis programming approach which could have applications for in situ monitoring of the relative amounts of the different polymorphs. 

General methods for the estimation of bismuth present in quantity include direct weighing as sulphide precipitation as sulphide, conversion to carbonate and ignition to oxide and precipitation as phosphate. Recently the use of EDTA as a titrant for bismuth has considerably simplified the determination of this metal in pharmaceutical mixtures. Bismuth forms a complex at pH 1 to 2 and at this degree of acidity few other metals likely to be encountered (with the exception of iron) interfere bismuth may therefore be selectively titrated in the presence of, say, aluminium, magnesium, or calcium. Various methods available have been discussed by Brookes and Johnson and the following general procedure is recommended ... 

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