Pharmaceutical formulations stabilization

M. A. Hanson and S. K. E. Rouan, Introduction to formulation of protein pharmaceuticals, in Stability of Protein Pharmaceuticals, Part B In Vivo Pathways of Degradation and Strategies for Protein Stabilization (T. J. Ahem and M. C. Manning, eds.), Plenum Press, New York, 1992, pp. 209-233. 

Tsuj i and Robertson achieved the separation of neomycin B, neomycin C and neamine as the trimethylsilyl ethers on a 6ft. column of 0.75% OV-1 on Gas Chrom Q at a temperature of 290°C. The same conditions have also been shown to separate neobiosamine B, neosamine and deoxystreptamine from neomycin and neamine. Hence the method could be used to study the stability of neomycin or to monitor the biosynthetic production process. Use of the procedure to assess the stability of neomycin in pharmaceutical formulations has been demonstrated by Van Giessen and Tsuji237 with trilaurin as internal standard. However,these authors recommended a 2ft. column packed with 3%... 

J. Brange, Chemical Stability of Insulin. 4. Mechanisms and Kinetics of Chemical Transformations in Pharmaceutical Formulation , Acta Pharm. Nordica 1992, 4, 209-222. 

Stability testing of drug compound Stability testing of pharmaceutical formulations and packagings... 

This reduction in self-aggregated AmB and the stability of the formulation suggested that LC-AmB could be a useful pharmaceutical formulation because it is generally accepted that the origin of toxicity toward mammalian cell membranes is free, self-associated AmB (2). 

PEG is a widely used molecule as a component in pharmaceutical formulations. PEG is particularly useful thanks to its low cost and various simple synthetic methods (26). PEG-lipid has been developed as a means of stabilizing conventional liposomes. A lipid moiety has been linked to the large PEGylated head in order to anchor the molecule to the particles. Instead of shielding a direct layer of polymer PEG around the particle, which would be less stable, the idea is to favor hydrophobic interactions between the PEG-lipid and the particle bilayer lipids. This anchor had led to two conformations of the PEG on the particle surface commonly called mushroom and brush regimes (27), representing a more condensed or extended conformations... 

The drug substance candidate that fulfills most of the properties described above will be selected for pharmaceutical formulation development. Focusing on bioavailability and stability, the requirements for a drug product are as follows ... 

Pharmaceutical product stability may be defined as the capability of a particular formulation to remain within its physical, chemical, microbiological, therapeutic,... 

Surfactants act as solubilizers, stabilizers, emulsiLers, and wetting agents. They can also causi toxicity and disrupt normal membrane structure. Surfactant toxicity is directly related to its concentration. This should be considered by the pharmaceutical formulator so levels below the toxic concentration will be used for a particular application. Many of the toxic effects of the surfactants are related to their physicochemical properties and their interaction with biological membranes and other macromolecular assemblies. The observed protein binding and lipid solubilization is directly... 

Maltodextrins (dextrose equivalent (DE) 4.0-7.0, 13.0-17.0 and 16.5-19.5) are proposed as novel chiral selectors for the construction of EPMEs for S-captopril assay [36]. The EPMEs can be used reliably for the assay of S-captopril as raw material and from pharmaceutical formulations as Novocaptopril tablets, using direct potentiometry. The best response was obtained when maltodextrin with higher DE was used for the electrode s construction. The best enantioselectivity and stability in time was achieved for the lower DE maltodextrin. L-Proline was found to be the main interferent for all proposed electrodes. The surface of the electrodes can be regenerated by simply polishing, obtaining a fresh surface ready to be used in a new assay. 

Oxidative instability is the second most common cause of chemical degradation of API in pharmaceutical formulations. If prior knowledge and/or preformulation stability experiments have predicted reactivity toward oxidative degradation, additional oxidative stress conditions can be included into excipient compatibility protocols in several ways. 

Wahbi et al. [32] used a spectrophotometric method for the determination of omeprazole in pharmaceutical formulations. The compensation method and other chemometric methods (derivative, orthogonal function, and difference spectrophotometry) have been applied to the direct determination of omeprazole in its pharmaceutical preparations. The method has been validated the limits of detection was 3.3 x 10 2 /ig/ml. The repeatability of the method was found to be 0.3-0.5%. The linearity range is 0.5-3.5 /ig/ml. The method has been applied to the determination of omeprazole in its gastro-resistant formulation. The difference spectrophotometric (AA) method is unaffected by the presence of acid induced degradation products, and can be used as a stability-indicating assay method. 

One rarely used but powerful means of maximizing both content uniformity (as mentioned above) and stability aspects of low-dose pharmaceuticals is the formation of inclusion complexes to increase both the drug load in the formulation as well as the stability of the API. One specific example is the complexation of ethinyl estradiol in the form of its /3-cyclodextrin clathrate for use in pharmaceutical formulations.23 This inclusion complex has been successfully applied in the development of an ultralow-dose formulation of this steroid.24... 

Highly disperse silica is widely used in pharmaceutical formulations as a filler, adsorbent, thickener etc.5 Their high hydrophilicity and the absence of emulsifying ability restrict their application. In contrast to hydroxylated silica, partially or fully hydrophobized silica may exhibit improved properties as a drug carrier. The main goal of this work is to study hydrophobized silica nanocomposites with immobilized vitamins C and E. Investigations of adsorption-desorption processes which involve silica nanoparticles and the antioxidants are described. Factors affecting the antioxidant stability have also been carefully considered. 

Pharmaceuticals formulated by the CRO and require formulation analysis for concentration, homogeneity, and stability Twice daily... 

Biopharmaceuticals or pharmaceuticals dissolved in Tyrodes s solution to obtain at least 5 different concentrations Biopharmaceuticals and pharmaceuticals formulated by the CRO and require formulation analysis for concentration, homogeneity, and stability dl-soltalol, a P-adrenergic antagonist that prolongs cardiac action potential by selectively blocking the rapidly activating delayed rectifier potassium current (IKr)... 

With the exception of S-metolachlor, all the molecules listed under the column Final Target are used in pharmaceutical formulations. Dilitiazem is a Ca2+ antagonist, while Cilazapril is an angiotensin-converting enzyme inhibitor. Levofloxacin is an antibacterial, and cilastatin is used as an in vivo stabilizer of the antibiotic imipenem. S-metolachlor is a herbicide sold under the trade name of DUAL MAGNUM. Although the structures of the final targets are more complex than those of the intermediates, enantioselective syntheses of the intermediates are the most crucial steps in the complex synthetic schemes of these molecules. 

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