Active pharmaceutical quantitation

However, compared with the traditional analytical methods, the adoption of chromatographic methods represented a signihcant improvement in pharmaceutical analysis. This was because chromatographic methods had the advantages of method specihcity, the ability to separate and detect low-level impurities. Specihcity is especially important for methods intended for early-phase drug development when the chemical and physical properties of the active pharmaceutical ingredient (API) are not fully understood and the synthetic processes are not fully developed. Therefore the assurance of safety in clinical trials of an API relies heavily on the ability of analytical methods to detect and quantitate unknown impurities that may pose safety concerns. This task was not easily performed or simply could not be carried out by classic wet chemistry methods. Therefore, slowly, HPLC and GC established their places as the mainstream analytical methods in pharmaceutical analysis. 

Quantitative and/or qualitative XRPD methods have been reported to determine the polymorphic content of clopidogrel bisulfate samples, and these have been summarized in Table 2.3. Koradia et al. [16] reported the qualitative analysis of clopidogrel bisulfate in both active pharmaceutical ingredients and tablet dosage forms. Based on the interplanar distances (d-spacing) associated with each polymorph, it was concluded that the molecular packing in Form-I was more dense than that of Form-II, indicating that Form-II would be less stable relative to Form-I. This result was similar with that reported by Bousquet [9]. 

Differences between methods from Tier 1 through Tier 3 are due to the extent of validation of the analytical figures of merit that is performed [3]. During early development of the active pharmaceutical ingredient and early dosage form development, emphasis is placed on speed and quantitation of the API. At this stage, methods rely on the use of short columns, fast flows, and very minimum validation to quickly identify the most desirable synthetic route for the API that will produce an adequate impurity profile (overall yield may not be optimized at this stage) and most desirable prototype formulations and excipients that will ultimately lead to the selection of the final formula-... 

Dr. Mukund Chorghade then introduces readers to the field of process chemistry the quest for the elucidation of novel, cost-effective, and scalable routes for production of active pharmaceutical ingredients. The medicinal chemistry routes used in the past have often involved the use of cryogenic reactions, unstable intermediates, and hazardous or expensive reagents. A case smdy of the development of a process for an antiepileptic drug is presented readers will also see how problems in the isolation, structure elucidation, and synthesis of metabolites were circumvented. Described is an interesting application of the technology of metalloporphyrins assisted metabolite prediction, estimation, quantitation and synthesis. 

T. Virtanen, S.L. Maunu, Quantitation of a polymorphic mixture of an active pharmaceutical ingredient with sohd state CPMAS NMR spectroscopy, Int. J. Pharm. 394 (1-2) (2010) 18-25. 

Li, W. and Worosila, G. D. Quantitation of active pharmaceutical ingredients and excipients in powder blends using designed multivariate calibration models by near-infrared spectroscopy. Int. J. Pharm. 295 213-219, 2005. 

The technique is highly suitable for quality assessment of the active pharmaceutical ingredients (APIs) or excipients. Quantitative NMR is useful in drug analysis to determine the level of impurities and to elucidate their structure, as well as to evaluate the content of residual solvents. It enables determination the isomeric composition, i.e., the ratio of diastereomers and the ee by means of chiral additives. It also allows for the measurement of molar ratios of (proton-ated) basic drugs and (deprotonated) organic acids in respective salts. 

A challenging task in material science as well as in pharmaceutical research is to custom tailor a compound s properties. George S. Hammond stated that the most fundamental and lasting objective of synthesis is not production of new compounds, but production of properties (Norris Award Lecture, 1968). The molecular structure of an organic or inorganic compound determines its properties. Nevertheless, methods for the direct prediction of a compound s properties based on its molecular structure are usually not available (Figure 8-1). Therefore, the establishment of Quantitative Structure-Property Relationships (QSPRs) and Quantitative Structure-Activity Relationships (QSARs) uses an indirect approach in order to tackle this problem. In the first step, numerical descriptors encoding information about the molecular structure are calculated for a set of compounds. Secondly, statistical and artificial neural network models are used to predict the property or activity of interest based on these descriptors or a suitable subset. 

A gene activity profile is a collection of quantitatively determined levels of gene products, found in one tissue or cell type, which is characteristic of the tissue, a disease process, a hormone response, a pharmaceutical intervention, etc. 

The different salts, esters, ethers, isomers, mixtures of isomers, complexes or derivatives of an active substance shall be considered to be the same active substance, unless they differ significantly in properties with regard to safety and/or efficacy, in which case additional safety and efficacy data are required. The same qualitative and quantitative composition only applies to the active ingredients. Differences in excipients will be accepted unless there is concern that they may substantially alter the safety or efficacy. The same pharmaceutical form must take into account both the form in which it is presented and the form in which it is administered. Various immediate-release oral forms, which would include tablets, capsules, oral solutions and suspensions, shall be considered the same pharmaceutical form for this purpose. 

Traditionally, in pursuit of their structure-activity relationships, medicinal chemists had focused almost exclusively on finding compounds with greater and greater potency. However, these SARs often ended up with compounds that were unsuitable for development as pharmaceutical products. These compounds would be too insoluble in water, or were not orally bioavailable, or were eliminated too quickly or too slowly from mammalian bodies. Pharmacologists and pharmaceutical development scientists for years had tried to preach the need for medicinal chemists to also think about other factors that determined whether a compound could be a medicine. Table 1.1 lists a number of factors that determine whether a potent compound has what it takes to become a drug. Experimentally, it was difficult to quantitate these other factors. Often, the necessary manpower resources would not be allocated to a compound until it had already been selected for project team status. 

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