Primary stabilizer

Hydrotalcite. Synthetic hydrotalcite minerals are gaining commercial acceptance for thein abiHty to costabiHze PVC ia the presence of other primary stabilizers (see Table 2). The performance of the mixed metal stabilizers are particularly boosted when an equal part level, about 2—3 phr, of hydrotalcite is added to the PVC formulation. These minerals function by trapping HCl within the layered lattice arrangement of atoms. The formula. 

A large number of hindered phenoHc antioxidants are based on the Michael addition of 2,6-di-/ f2 -butylphenol and methyl acrylate under basic catalysis to yield the hydrocinnamate which is a basic building block used in the production of octadecyl 3-(3,5-di-/ f2 butyl-4-hydroxyphenyl)propionate, [2082-79-3], tetrakis(methylene-3(3,5-di-/ f2 butyl-4-hydroxylphenyl)propionate)methane [6683-19-8], and many others (63,64). These hindered phenolic antioxidants are the most widely used primary stabilizers in the world and are used in polyolefins, synthetic and natural mbber, styrenics, vinyl polymers, and engineering resins. 2,6-Di-/ f2 -butylphenol is converted to a methylene isocyanate which is trimerized to a triazine derivative... 

FIGURE 15.4 Primary stabilization via radical scavenging by hindered pbenobcs. 

SN, reactions of primary stabilized organolithium compounds on polyalkylmethacrylates affords a very versatile synthetic route to model ketonic copolymers substitution is selective and quantitative up to DSm of 0.60,and it is easily monitored by the initial... 

The endo selectivity in many Diels-Alder reactions has been attributed to attractive secondary orbital interactions. In addition to the primary stabilizing HOMO-LUMO interactions, additional stabilizing interactions between the remaining parts of the diene and the dienophile are possible in the endo transition state (Figure 3). This secondary orbital interaction was originally proposed for substituents having jr orbitals, e.g. CN and CHO, but was later extended to substituents with tt(CH2) type of orbitals, as encountered in cyclopropene57. 

The level 3 method is used until synthetic routes and formulations have been finalized and forced degradation and preliminary stability studies have been conducted i.e., until the components that need to be separated in the final DS and in the final DP have been clearly determined. At this juncture, the focus shifts to the development of fast, robust and transferable final methods to be used for primary stability studies and post-approval analyses. Freqnently, separate methods are developed for DS and DP since the goals of each method are different (see Section I). Orthogonal methods continue to be of importance to troubleshoot any questions that may arise during the subsequent life cycle of the drug. 

API Development. The synthetic route will be finalized and a formal primary stability study will be undertaken to assess the stability of the API. 

Formulation Development. The formulation is finalized based on the experience gained in the manufacture of clinical phase I and II trial materials. Scale-up of the manufacturing process will be completed to qualify the manufacturing capability of the facility. The primary stability study is initiated to assess the stability of the drug product. 

According to the stabilization method used in German factories, after primary stabilization in boilers, the nitrocellulose was subjected to a short kiering in autoclaves made from acid-resistant steel with a hot-water circulation (Fig. 153). 

In addition to their role in primary stabilization related to viscosity increase, some hydrocolloids (particularly carrageenan) are traditionally used as secondary stabilizers. Many of the primary stabilizing hydrocolloids, including locust bean gum and carboxy methyl cellulose induce precipitation of the milk proteins in the mix. This phenomenon in ice cream mix is known as wheying-off, and may be due to direct protein-polysaccharide binding and/or protein-polysaccharide incompatibility in the water phase40. The latter phenomenon may be due to decreased solvent quality due to the competition between protein and polysaccharide for solubilisation. 

The cumyl cation (4) has been the subject of an X-ray crystallographic study, as its hexafluoroantimonate salt at —124 °C.31 It is nearly planar (8 ° twist), with a short bond between the C+ and the ring (1.41 A), consistent with benzylic delocalization. The Me—C+ bonds are also shortened, indicative of hyperconjugative interaction.31 However, calculations are taken to show that hyperconjugation is not important in isolated benzyl cations e.g. structures such as (6) are not important contributors to the overall structure of (5).32 The stabilization provided by alkyl groups would thus be because of their polarizability, and the Baker-Nathan effect would be due to steric hindrance to solvation.32 The heats of formation of some a-mcthylbcnzyl cations indicate that the primary stabilization in these species comes from the a-substitucnts, and that the stabilization provided by the aromatic ring is secondary.33... 

The optimized formulation then is prepared for phase III pivotal clinical trials. Followed by manufacturing process optimization and scale-up, the three batches of the dmg product are manufactured for primary stability evaluation at product launch sites. The information on the manufacture, scale-up, control, and stability is used for product registration with regulatory agencies. 

Solids Wetting. In most crude oil, solids such as iron sulfide, silt, clay, drilling mud solids, and paraffin complicate the demulsification process. Often such solids are the primary stabilizing material, and their removal is all that is necessary to achieve satisfactory treatment. To remove solids from the interface, they can either be dispersed in the oil or water-wetted and removed with the water. 

Where long term data are not amenable to statistical analysis, but relevant supporting data are provided, the proposed shelf life can be up to one-and-a-half times, but should not be more than 6 months beyond, the period covered by long term data. Relevant supporting data include satisfactory long term data from development batches that are (/) made with a closely related formulation to, ( /) manufactured on a smaller scale than, or (/7/) packaged in a container closure system similar to, that of the primary stability batches. 

Where applicable, an appropriate statistical method should be employed to analyze the long term primary stability data. The purpose of this analysis is to establish, with a high degree of confidence, a shelf life during which a quantitative attribute will remain within acceptance criteria for all future batches manufactured, packaged, and stored under similar circumstances. 

---