Formatting Stability Reports

Submitted information should be cumulative and in tabular form. 

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The stabilization reactions of alkylcarbenes were used preparatively in some cases. The diazirine derived from adamantanone gave the dehydroadamantane (2l7) thermally in 96% yield 73ZOR430). Alkene formation was reported for a steroid with its C-3 atom part of a diazirine ring. At 140 °C a A-2-unsaturated steroid was formed 65JA2665). 

DEGRAD STABILjcIs Section 1.8.4 The analysis of stability reports often suffers from the fact that the data for each batch of product is scrutinized in isolation, which then results in a see-no-evil attitude if the numerical values are within specifications. The analyst is in a good position to first compare all results gained under one calibration (usually a day s worth of work) irrespective of the products/projects affected, and then also check the performance of the calibration samples against experience, see control charts, Section 1.8.4. In this way, any analytical bias of the day will stand out. For this purpose a change in format from a Time-on-Stability to a Calendar Time depiction is of help. 

The FDA Draft Stability Guidance includes a discussion on the content and format of stability reports. The API stability section is generally straightforward however, the drug product stability section can have many parts and should be especially well organized. In addition to the elements discussed in FDA Draft Stability Guidance, the items included in Example 4 should be considered in order to facilitate review. 

A solvent extraction method was used to determine, the stability of NiCU and NiSCN complexes, among others. The aqueous phase was 1 M NaC104 solution, while the organic phase was CCI4 containing 0.05 M thenoyltrifluoroacetone and 0.03 M trioctyl-phosphine. The concentration of nickel(II) was 1.0 x 10 M, while that of the complex forming anion varied up to 0.4 M for thiocyanate and ca 0.85 M in case of chloride. As the amount of metal extracted was very low in the case of chloride, even at high chloride concentrations, only the formation constant reported for the thiocyanate complex is considered in this review. 

Desmaison et al. conducted studies on Arabian crudes and noted the emulsion formation was correlated with two factors - photo-oxidation exposure and amount of asphaltenes (16). The photo-oxidation was found to occur on the aromatic fractions of the oil. Asphaltenes were found to become structured with time and this was associated with emulsion formation. Miyahara reported that the stability of emulsions was primarily controlled by the composition of the oil, specifically that which resided in flie hexane-insoluble fraction of the oil, but he did not define what fliis content was (17). Miyahara also reported that salt and freshwater emulsions showed relatively similar stabilities, alfliough in one case the salt-water emulsion appeared to be more stable. Payne and Phillips reviewed the subject in detail and reported on their on experiments of emulsification wifli Alaskan cmdes in fire presence and absence of ice (18). Their studies showed fliat emulsion formation could occiff in an ice field, thus indicating that fliere was sufficient energy in this environment and that the process could occur at relatively low temperatures. 

Uniform bimetallic copper-palladium colloids (the metals are completely miscible) have been prepared by thermolysis of mixtures of the acetates in high boiling solvents such as bromobenzene, xylenes, and methyl- o-butyl ketone [86] in the absence of polymer stabilizers. The resulting agglomerated bimetallic particles often contained CuO in addition to the metals. Smaller particle sizes and narrower size distributions without oxide formation were reported to result from the analogous reaction in 2-ethoxyethanol in the presence of PVR [38] In both cases the homogeneous composition of the particles was established during the electron microprobe analysis used to determine the Cu Pd ratio in the individual particles. 

Photochemical cleavage of metal-carbon bonds constitutes a brief part of a recent review on the photochemistry of metal carbonyls. Reviews of metal-alkyl and -aryl complexes have also appeared, one of which is concerned solely with metals in Groups IV— VII. The other deals with the formation, stability, and decomposition pathways of transition metal-carbon a-bonds, subjects of much interest in recent years. Consequently the recent isolation of the first stable methylene complex [Ta(Me)(CHa)(jj-C6H6)2] and its unequivocal characterization by a single-crystal JlT-ray diffraction study is of great interest in view of the probability that related derivatives are involved in the recently reported (see Vol, 4, p. 293) examples of a-hydride elimination in metal alkyls. 

An ab initio study of the addition of lithium aluminium hydride (LAH) to acetonitrile and malononitrile is reported the free anions generated by hydride addition show clear preferences for the enamide (RCH CH=NH RCH=CHN H) over the imide (RCH2CH=N ). Lithium ion pair formation stabilizes both tautomers, the localized imide is stabilized slightly more than the enamide, and the enamide preference is somewhat reduced but persists. The alane-complexed lithium ion pairs result in a small imide preference for the LAH adduct of acetonitrile and a dramatically reduced enamide preference for the LAH adduct of malononitrile. Alane affinities were determined for the lithium ion pairs formed by LiH addition to the nitriles. The alane binding greatly affects the imide-enamide equilibria such that alane complexation might even provide... 

Dimerization is reportedly catalyzed by pyridine [110-86-1] and phosphines. Trialkylphosphines have been shown to catalyze the conversion of dimer iato trimer upon prolonged standing (2,57). Pyridines and other basic catalysts are less selective because the required iacrease ia temperature causes trimerization to compete with dimerization. The gradual conversion of dimer to trimer ia the catalyzed dimerization reaction can be explained by the assumption of equiUbria between dimer and polar catalyst—dimer iatermediates. The polar iatermediates react with excess isocyanate to yield trimer. Factors, such as charge stabilization ia the polar iatermediate and its lifetime or steric requirement, are reported to be important. For these reasons, it is not currently feasible to predict the efficiency of dimer formation given a particular catalyst. 

Although examples in the Kureha patent Hterature indicate latitude in selecting hold times for the low and high temperature polymerization periods, the highest molecular weight polymers seem to be obtained for long polymerization times. The addition of water to PPS polymerizations has been reported to effect polymer stabilization (49), to improve molecular weight (50,51), to cause or enhance the formation of a second Hquid phase in the reaction mixture (52), and to help reprecipitate PPS from NMP solution (51). It has also been reported that water can be added under pressure in the form of steam (53). 

Stability. The thermodynamic stabiUty of coordination compounds in solution has been extensively studied (12). The equiUbrium constants may be reported as stabiUty or formation constants. 

Perhaps the most firmly based report for the formation of an azete involves flash pyrolysis of tris(dimethylamino)triazine (303). This gave a red pyrolysate believed to contain the highly stabilized azete (304) on the basis of spectroscopic data. The putative azete decomposed only slowly at room temperature, but all attempts to trap it failed (73AG(E)847). Flash pyrolysis of other 1,2,3-triazines gives only acetylenes and nitriles and it is not possible to tell whether these are formed by direct <,2-l-<,2-l-<,2 fragmentation of the triazine or by prior extrusion of nitrogen and collapse to an azete (81JCR(S)162). 

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