Pharmaceuticals optimization methods

The purification of value-added pharmaceuticals in the past required multiple chromatographic steps for batch purification processes. The design and optimization of these processes were often cumbersome and the operations were fundamentally complex. Individual batch processes requires optimization between chromatographic efficiency and enantioselectivity, which results in major economic ramifications. An additional problem was the extremely short time for development of the purification process. Commercial constraints demand that the time interval between non-optimized laboratory bench purification and the first process-scale production for clinical trials are kept to a minimum. Therefore, rapid process design and optimization methods based on computer aided simulation of an SMB process will assist at this stage. 

This optimization method, which represents the mathematical techniques, is an extension of the classic method and was the first, to our knowledge, to be applied to a pharmaceutical formulation and processing problem. Fonner et al. [15] chose to apply this method to a tablet formulation and to consider two independent variables. The active ingredient, phenylpropanolamine HC1, was kept at a constant level, and the levels of disintegrant (corn starch) and lubricant (stearic acid) were selected as the independent variables, X and Xj. The dependent variables include tablet hardness, friability, volume, in vitro release rate, and urinary excretion rate in human subjects. 

In summary, optimization of the environmental profile of APIs starts from a new or already known lead structure. During the pharmaceutical optimization process, which involves systematic variation of parts of the molecule, the biodegradability of the resulting structures is also monitored. Candidates that possess both better pharmaceutical and environmental properties advance to the next round of optimization. With the help of modem in silico methods (e.g., QSARs, expert systems) this can be done systematically, quickly, and cheaply, without the need to synthesize all the molecules of interest [132]. In a similar way, we were able to improve the biodegradability of a new lead structure by systematically modifying the lead molecule while retaining the necessary low octanol-water partition coefficient. As... 

Capella-Peiro et al. (28) used a 3 full factorial design to optimize the capillary zone electrophoresis (CZE) separation of a group of seven antihistamines (brompheniramine, chlorpheniramine, cyproheptadine, diphenhydramine, doxylamine, hydroxyzine, and loratadine). In this case, critical parameters such as pH (a concentration of 20 mM phosphate was kept constant in all the experiments) and the applied voltage were studied to evaluate their effect on the resolution and efficiency. Maximum response was achieved at pH 2.0 and an applied voltage of 5 kV. After a repeatability study to check the precision of the electrophoretic method, as well as a suitable calibration, the usefulness of this optimized method was demonstrated through the determination of the listed histamines in pharmaceuticals, urine, and serum samples (recoveries were in agreement with the stated contents). Urine samples were diluted and directly injected in the CE system, while serum samples were previously extracted by means of a solid-phase extraction (SPE) procedure. 

Spectrometric methods are usually recommended by pharmacopoeias for the assay of pharmaceutical products.55 These require both a separation step and a calibration graph. The resolution of a spectrometric method used for assay of a ternary or quaternary mixture of drugs is not good when a certain, well-known calibration graph is used. To obtain the maximum reliability for data processing it is necessary to use the PLS methodology222 because it eliminates the need for sample pretreatment. This model represents essentially an optimization method that can be applied to the problem of the experimental design. 

The analysis and mathematical modelling of mixtures is significant in pharmaceutical formulation and these present certain particular problems. The final chapters cover methods for optimizing formulations and also treat "mixed" problems where process variables and mixture composition are studied at the same time. In both chapters 9 and 10 we continue to illustrate the graphical and numerical optimization methods described earlier. 

Selected Applications of Electroseparation Methods for Miscellaneous Endocrine Disrupters Preconcentration Procedure and Pharmaceuticals Optimal in Environmental Samples and Detection ... 

Markopoulou, C.K., Kagkadis, K.A., and Koundourellis J.E., 2002. An optimized method for the simultaneous determination of vitamins Bl, B6, B12 in multivitamin tablets by high performance hquid chromatography. Journal of Pharmaceutical and Biomedical Analysis. 30 1403 1410. 

Besides the presented methods there are a lot of other ways to generate hits in pharmaceutical industry. Methods like SOSA (selective optimization of side activities) [16] and fragment-based approaches are presented in other chapters and are therefore not discussed here. We have tried to provide an overview of the most often used - at least from our viewpoint - lead generation method in this chapter. It is the authors experience that no single lead generation method... 

Method development remains the most challenging aspect of chiral chromatographic analysis, and the need for rapid method development is particularly acute in the pharmaceutical industry. To complicate matters, even structurally similar compounds may not be resolved under the same chromatographic conditions, or even on the same CSP. Rapid column equilibration in SFC speeds the column screening process, and automated systems accommodating multiple CSPs and modifiers now permit unattended method optimization in SFC [36]. Because more compounds are likely to be resolved with a single set of parameters in SFC than in LC, the analyst stands a greater chance of success on the first try in SFC [37]. The increased resolution obtained in SFC may also reduce the number of columns that must be evaluated to achieve the desired separation. 

Since the U.S. vs. Barr decision in 1993 (relevant to pharmaceuticals and related fields, rules applied by the Federal Food Drug Administration, FDA), outlier tests may no longer be applied to physicochemical tests, under the assumption that such test methods, having been optimized and validated for the particular set of circumstances, rarely produce outliers. These tests may not be applied to CU results at all. Good manufacturing practices mandate that operators work according to pre-set procedures and write down any observed irregularities as they... 

Takayama K, Fujikawa M, Nagai T. Artificial neural networks as a novel method to optimize pharmaceutical formulations. Pharm Res 1999 16 1-6. 

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