Impurities approach

Purity determination is an essential component of the assessment of the quality of any drug. However, the purity determination of biopharmaceuticals is not as straightforward as for small-molecule pharmaceuticals because biopharmaceuticals are structurally complex and have a wide range of potential impurities. Approaches usually involve the judicious choice of a combination of methods that will enable the detection and quantitation of impurities from which an overall purity assessment can be made. CE-generated data now play a significant role in such purity assessments. 

The theory of "impurity" or defect absorption Intensities in semiconductors has been studied by Rashba ( 1). By use of the Fredholm method, he finds that if the absorption transition occurs at k=0 and if the discrete level associated with the impurity approaches the conduction band, the intensity of the absorption line increases. The explanation offered for this intensity behavior is that the optical excitation is not localized in the impurity but encompasses a number of neighboring lattice points of the host crystal. Hence, in the absorption process, light is absorbed by the entire region of the crystal consisting of the impurity and its surroundings. 

The spectra analysis within a single-impurity approach including in separate terms the f-mixing with valence and conduction bands appears to be very successful for these materials. 

An important approach to the study of nucleation of solids is the investigation of small droplets of large molecular clusters. Years ago, Turnbull showed that by studying small droplets one could eliminate impurities in all except a few droplets and study homogeneous nucleation at significant undercoolings [13]. 

Since shallow-level impurities have energy eigenvalues very near Arose of tire perfect crystal, tliey can be described using a perturbative approach first developed in tire 1950s and known as effective mass theoiy (EMT). The idea is to approximate tire band nearest to tire shallow level by a parabola, tire curvature of which is characterized by an effective mass parameter m. ... 

By using a laser with less power and the beam spread over a larger area, it is possible to sample a surface. In this approach, after each laser shot, the laser is directed onto a new area of surface, a technique known as surface profiling (Figure 2.4c). At the low power used, only the top few nanometers of surface are removed, and the method is suited to investigate surface contamination. The normal surface yields characteristic ions but, where there are impurities on the surface, additional ions appear. 

Chemical Conversion. In both on-site and merchant air separation plants, special provisions must be made to remove certain impurities. The main impurity of this type is carbon monoxide, CO, which is difficult to separate from nitrogen using distiHation alone. The most common approach for CO removal is chemical conversion to CO2 using an oxidation catalyst in the feed air to the air separation unit. The additional CO2 which results, along with the CO2 from the atmosphere, is then removed by a prepuritication unit in the air separation unit. 

Ion implantation (qv) has a large (10 K/s) effective quench rate (64). This surface treatment technique allows a wide variety of atomic species to be introduced into the surface. Sputtering and evaporation methods are other very slow approaches to making amorphous films, atom by atom. The processes involve deposition of a vapor onto a cold substrate. The buildup rate (20 p.m/h) is also sensitive to deposition conditions, including the presence of impurity atoms which can faciUtate the formation of an amorphous stmcture. An approach used for metal—metalloid amorphous alloys is chemical deposition and electro deposition. 

Rehable deterrnination of the solubihty of sihca in water has been comphcated by the effects of impurities and of surface layers that may affect attainment of equihbrium. The solubihty behavior of sihca has been discussed (9,27). Reported values for the solubihty of quartz, as Si02, at room temperature are in the range 6—11 ppm. Typical values for massive amorphous sihca at room temperature are around 70 ppm for other amorphous sihcas, 100—130 ppm. Solubihty increases with temperature, approaching a maximum at about 200°C. Solubihty appears to be at a minimum at about pH 7 and increases markedly above pH 9 (9). 

A study was conducted to measure the concentration of D-fenfluramine HCl (desired product) and L-fenfluramine HCl (enantiomeric impurity) in the final pharmaceutical product, in the possible presence of its isomeric variants (57). Sensitivity, stabiUty, and specificity were enhanced by derivatizing the analyte with 3,5-dinitrophenylisocyanate using a Pirkle chiral recognition approach. Analysis of the caUbration curve data and quaUty assurance samples showed an overall assay precision of 1.78 and 2.52%, for D-fenfluramine HCl and L-fenfluramine, with an overall intra-assay precision of 4.75 and 3.67%, respectively. The minimum quantitation limit was 50 ng/mL, having a minimum signal-to-noise ratio of 10, with relative standard deviations of 2.39 and 3.62% for D-fenfluramine and L-fenfluramine. 

Eurther heat treatment in excess of 2000°C is referred to as graphitization. Eiber stmcture further densifies as molecular packing and orientation increase. At temperatures of 3000°C or above, the fiber stmcture begins to approach a truly graphitic stmcture with three-dimensional order. Typically, fiber strain to failure decreases as the carbonization temperature exceeds 1500°C because of reaction of impurities with the carbon fiber and the development of an increasingly flaw-sensitive graphitic stmcture (31,34)... 

Color from Transition-Metal Compounds and Impurities. The energy levels of the excited states of the unpaked electrons of transition-metal ions in crystals are controlled by the field of the surrounding cations or cationic groups. Erom a purely ionic point of view, this is explained by the electrostatic interactions of crystal field theory ligand field theory is a more advanced approach also incorporating molecular orbital concepts. 

Successful operation of the gaseous diffusion process requires a special, fine-pored diffusion barrier, mechanically rehable and chemically resistant to corrosive attack by the process gas. For an effective separating barrier, the diameter of the pores must approach the range of the mean free path of the gas molecules, and in order to keep the total barrier area required as small as possible, the number of pores per unit area must be large. Seals are needed on the compressors to prevent both the escape of process gas and the inflow of harm fill impurities. Some of the problems of cascade operation are discussed in Reference 16. 

High mass-transfer rates in both vapor and hquid phases. Close approach to eqiiilihriiim. Adiabatic contact assures phase eqiiilihriiim, Only moderate mass-transfer rate in liquid phase, zero in sohd. Slow approach to equilibrium achieved in brief contact time. Included impurities cannot diffuse out of solid. Sohd phase must be remelted and refrozen to allow phase equilibrium. 

This approach enables also to substantiate acceptance criteria for detection and qualification limits in impurity control method validation. 

The important question, then, is not whether a substance is pure but whether a given sample is sufficiently pure for some intended purpose. That is, are the contaminants likely to interfere in the process or measurement that is to be studied. By suitable manipulation it is often possible to reduce levels of impurities to acceptable limits, but absolute purity is an ideal which, no matter how closely approached, can never be attained. A negative physical or chemical test indicates only that the amount of an impurity in a substance lies below a certain sensitivity level no test can demonstrate that a specified impurity is entirely al ent. 

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