Recovery excipients

Niclosamide and its dosage forms were spectrophotometrically estimated by reaction with aqueous 4-aminophenazone in the presence of ammonia and measurement of absorbance of the resulting oxidative coupling product at 520 nm [50], Beer s law was obeyed in the concentration range 1.25-10.0 pg/mL the relative standard deviation was 1.51% and the recovery 98.9 99.6%. Dosage form excipients did not interfere. 

Besada et al. [13] described spectrophotometric methods for determination of penicillamine in pure and dosage forms. Penicillamine was measured spectrophoto-metrically in 0.1 M HC1 (at 195 nm) or in 0.1 M NaOH (at 238 nm). Both methods gave recoveries of 100% with good precision. For determination of the drug in tablets, in the presence of excipients, ground samples were extracted with each of these solvents and the difference in absorbance at 238 nm between the two solutions were measured. The recovery of the drug from commercial tablets was 99.8%, with a coefficient of variation of 0.38%. The three methods were suitable for 4—130 ppm of the drug. 

Vishwavidyalaya et al. [22] used a difference-spectrophotometric method for the estimation of primaquine phosphate in tablets. One portion of powdered tablets, equivalent to 7.5 mg of primaquine phosphate, was extracted with hydrochloric acid-potassium chloride buffer (pH 2) and a second portion was extracted with phosphate buffer (pH 10). Primaquine phosphate was determined from the difference in absorbance of the acid and alkaline extracts at 254.2 nm. The calibration graph was rectilinear from 2 to 14 pg/mL of primaquine phosphate. Recovery was 98.6% and no interference was observed from excipients. Results compared with those by the British Pharmacopoeial method. 

A method recommended for adoption as official, first action (27). The method in which methimazole is separated from tablet excipients by column chromatography on Celite 545 with chloroform as the eluent and then quantitatively measured and identified by IR spectrophotometry. This method was studied collaborative-ly by 10 analysts average recoveries from two simulated and two tablets mixtures ranged from 96.6% + 1.0 to 101.1% + 0.9 (28). 

Rather than using the initial donor concentration, the final donor concentration at the termination of incubation can be used. Another approach to reduce nonspecific binding involves the addition of serum proteins [80, 120] or micelleforming excipients, such as Gelucire 44/14, Cremophor EL, or TPGS, [45] to the receiver compartment, leading to an improved assay recovery and better predictability of the model [64],... 

Figure 3.9. Generalized overview of the industrial-scale manufacture of recombinant E2 classical swine fever-based vaccine, using insect cell culture production systems. Clean (uninfected) cells are initially cultured in 500-1000 litre bioreactors for several days, followed by viral addition. Upon product recovery, viral inactivating agents such as /i-propiolactone or 2-bromoethyl-iminebromide are added in order to destroy any free viral particles in the product stream. No chromatographic purification is generally undertaken as the product is substantially pure the cell culture media is protein-free and the recombinant product is the only protein exported in any quantity by the producer cells. Excipients added can include liquid paraffin and polysorbate 80 (required to generate an emulsion). Thiomersal may also be added as a preservative. The final product generally displays a shelf-life of 18 months when stored refrigerated...

The discipline of analytical chemistry is wide and catholic. It is often difficult for a food chemist to understand the purist concerns of a process control chemist in a pharmaceutical company. The former deals with a complex and variable matrix with many standard analytical methods prescribed by Codex Alimentarius, for which comparability is achieved by strict adherence to the method, and the concept of a true result is of passing interest. Pharmaceuticals, in contrast, have a well-defined matrix, the excipients, and a well-defined analyte (the active) at a concentration that is, in theory, already known. A 100-mg tablet of aspirin, for example, is likely to contain close to 100 mg aspirin, and the analytical methods can be set up on that premise. Some analytical methods are more stable than others, and thus the need to check calibrations is less pressing. Recovery is an issue for many analyses of environmental samples, as is speciation. Any analysis that must... 

The accuracy of the method related to the excipient is achieved by assay of three preparations at 50%, 100%, and 150% of the proposed concentration by spiking the excipient. The mean recovery at each level should be between 97 and 103% (Table 6.2). 

Active and excipient chemical ingredients used in drug products may therefore be considered as BPCs. These materials can be made by chemical synthesis, fermentation, enzymatic reactions, recombinant DNA, recovery from natural materials, or a combination of the above. 

Like APIs, pharmaceutical excipients are made by chemical synthesis, fermentation, recovery from natural materials, and so on. Often purification procedures may not be employed in the manufacture of such pharmaceutical excipients as clays, celluloses, starches, and natural gums. In addition, the physical and chemical change of certain excipients during processing is not uncommon. Unlike APIs, many excipients have complicated chemical and physical structures that do not yield easily to modern analytical and chromatographic methods. 

Murakami et al. [82] developed and validated a sensitive HPLC technique to quantify omeprazole in delayed release tablets. The analysis was carried out using a RP-Cig column with UV-VIS detection at 280 nm. The mobile phase was diluted with phosphate buffer (pH 7.4) and acetonitrile (70 30) at a flow-rate of 1.5 ml/min. The parameters used in the validation process were linearity, range, quantification limit, accuracy, specificity, and precision. The retention time of omeprazole was about 5 min with symmetrical peaks. The linearity in the range of 10-30 ng/ml presented a correlation coefficient of 0.9995. The excipients in the formulation did not interfere with the analysis and the recovery was quantitative. Results were satisfactory and the method proved to be adequate for quality control of omeprazole delayed-release tablets. 

The most commonly described USP procedure for quantification is the scrap and elution approach. Low analyte recoveries can occur but can be minimized by using polar organic solvents such as methanol, ethanol, or acetone. Generally, analytes with high-Rf values can be desorbed with high recoveries by using the mobile phase. One example of this procedure is the USP assay procedure of the steroid methyl prednisolone acetate in cream formulation. This steroid is separated from its excipients by TLC, extracted from the sorbent, derivatized, and measured spectrophotometrically. 

To address the challenges in low-dose dmg product development, we recently initiated an excipient library approach, which follows the philosophy, an ounce of prevention is worth a pound of cure. The idea was to create a library of excipient-related information such as chromatographic background, stability, compatibility, and effect on dmg recovery and release. This library serves as a general tool for low-dose dmg development. Using the library, development teams are able to screen for the most appropriate excipients at the development planning/design phase on the basis of both formulation and analytical requirements. This approach aims to reduce analytical development difficulties where possible. 

Kang, F., Jiang, G., Hinderliter, A., DeLuca, P. R, and Singh, J. (2002), Lysozyme stability in primary emulsion for PLGA microsphere preparation Effect of recovery methods and stabilizing excipients, Pharm. Res., 19, 629-633. 

To overcome this problem, it has been proposed to use an adequate excipient, preventing the recovery of the crystallinity, leading in some cases to the preparation of solid solutions into the die of the tableting machine. 

Plastic Deformation Plastic deformation results from the combination of thermal and mechanical effects. The thermoplastic excipient was subjected to a temperature above its glass transition temperature (Tg) and to a high-frequency mechanical pressure that can avoid the elastic recovery of the material. 

Recovery of an active or degradation product during the sample preparation is most likely due to adsorption on the undissolved excipients or capsule shells. The following case study [28] illustrates this point very well. 

The results from these two experiments (kinetic and thermodynamic) will show whether the regular extraction procedure is complete or not. Most hkely, for modified-release drug products, time is essential (higher recovery over time, but watch out for solution stabihty ). The change in volume will have an impact if the solubihty of an API is on the border of the solubility limit in that particular sample preparation solvent (in the presence of excipients). If the latter is the case, then the procedure should be modified to extract with higher volume of sample preparation solvent and/or change the pH or composition of the solvent. 

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