Stability indicator, balances

Even if HPLC is chosen as the main stability indicating method, CE will be useful as orthogonal technique, especially in cases where the reason of mass balance deviations is unclear. In addition, due to its increased peak capacity and selectivity in comparison to HPLC, the detection of possible enantiomers, stereoisomers, and position isomers, having the same molecular weight and equal/similar spectra as the drug substance may be separated by a secondary CE method. 

Mass balance is also useful in method validation (1,3,4). In order to demonstrate that analytical methods are stability indicating, unstressed and stressed materials are often compared. An increase in degradation products that correlates well with loss of parent drug aids in demonstrating that the methods can be used to accurately assess degradation. 

QIE Evaluation of Stability Data Page 2 Factors that can cause an apparent lack of mass balance should be considered, including, for example, the mechanisms of degradation and the stability-indicating capability and inherent variability of the analytical procedures... 

A question often brought up in discussions of forced degradation and SIMs is whether mass balance should be achieved in all cases. Evidence that the total material detected in the stressed samples is equal to the starting input is certainly helpful for demonstrating the stability-indicating ability of the method. Mass balance results of 96-102% were reported for dipyridamole even with significant degradation of up... 

To keep inaccuracy and imprecision of a balance to their intrinsic (or ideal) values, a balance should be placed completely free from disturbances. However in pharmacy preparation imperfect placing is the rule. By using a stability indicator the additional imprecision due to imperfect placement can be restricted but it is generally acknowledged that the additional imprecision due to imperfect placement has to be monitored (see Sect. 29.1.6). 

All balance types for pharmacy preparation preferably have an automatic internal calibration option and can operate in connection with software functions, e.g. for in-process control. The balance should be equipped with a stability indicator so that the weight is only registered or printed after stabilisation of the balance. Draft shields are important, especially for weighing in controlled (ventilated ) environments. Special functions such as piece counting (for counting tablets or capsules the so-called pill counter ) may be advantageous. 

It should be checked to see if the balance is levelled. If this is not the case, the balance should be aligned using the adjustable feet while monitoring the level indicator. It should be checked that the balance displays exactly zero at the start of each weighing (stability indicator, Sect. 29.1.3.1). The balance can then be tared. 

Forced degradation samples are used in the process of developing stability-indicating methods early in development prior to initiating formal stability studies. The samples are analyzed for API peak purity (coeluting impurities), specificity, and mass balance. Efforts are also focused on determination degradation pathways/mechanisms for API and DP. 

The scope of ICH QIE addresses the evaluation of stability data that should be submitted in registration applications for new molecular entities and their associated drug products. A systematic approach should be adopted in the presentation and evaluation of the stability information. The stability information should include, as appropriate, results from physical, chemical, biological, and microbiological tests. Mass balance should be assessed and the factors that can cause an apparent lack of mass balance the mechanism of degradation and the stability-indicating capability and inherent variability of the analytical procedures. 

Mercapto derivatives of furan, thiophene, selenophene (77ACS(B)198) and pyrrole (72AJC985) all exist predominantly in the thiol form. 2-Mercaptobenzothiophene is also a thiol (70JCS(C)243i) whereas 2-mercaptoindole is mainly indoline-2-thione (89) (69CPB550). The finely balanced nature of this system is indicated by the fact that a 3-aryl, but not a 3-alkyl, substituent will stabilize the 2-thiol form, whereas for 3-aryl-fV-methyl derivatives the 2-thione tautomer is preferred (71CC836). 

Room temperature CO oxidation has been investigated on a series of Au/metal oxide catalysts at conditions typical of spacecraft atmospheres CO = 50 ppm, COj = 7,000 ppm, H2O = 40% (RH) at 25 C, balance = air, and gas hourly space velocities of 7,000- 60,000 hr . The addition of Au increases the room temperature CO oxidation activity of the metal oxides dramatically. All the Au/metal oxides deactivate during the CO oxidation reaction, especially in the presence of CO in the feed. The stability of the Au/metal oxide catalysts decreases in the following order TiOj > FejO, > NiO > CO3O4. The stability appears to decrease with an increase in the basicity of the metal oxides. In situ FTIR of CO adsorption on Au/Ti02 at 25 C indicates the formation of adsorbed CO, carboxylate, and carbonate species on the catalyst surface. 

A kinetically stabilized diarylgermylene, Tb(Tip)Ge, is also stable in hexane solution with no tendency to dimerize. The structure has not yet been measured but it was characterized as the base-free mononuclear transition metal complex formed with the reactive M(CO)s. THF adduct (M = Mo,W). The crystal structure of the W complex466 shows Ge=W = 259.3 pm, Ge-Tb = 198.8 pm, Ge-Tip = 199.9 pm, CGeC = 108.4°, TbGeW = 138.9° and TipGeW = 112.2°. Thus the Ge is pyramidal and the structure is obviously the result of a balance of steric repulsions between the carbonyls, Tb, and Tip. Older work on similar Ge=W compounds, RR,Ge=W(CO)5 with RR = Cp (Cl) or (Bsi)2467, show Ge=W lengths of 251.1 and 263.2 pm, respectively, indicating the combined steric and electronic effects. 

The primary effect of the anode modification on the enhancement in luminous efficiency and the increased stability of OLEDs can be attributed to an improved hole-electron current balance. By choosing an interlayer with a suitable thickness of a few nanometers, anode modification enables engineering of the interface electronic properties. The above results indicate that conventional dual-layer OLEDs of ITO/NPB/Alq3/cathode have an inherent weakness of instability that can be improved by the insertion of an ultrathin interlayer between ITO and HTL. The improvements are attributed to an improved ITO-HTL interfacial quality and a more balanced hole electron current that enhances the OLED performance. 

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