Pharmaceutical formulations physical stability

Surfactants are useful in formulating a wide variety of disperse systems. They are required not only during manufacture but also for maintaining an acceptable physical stability of these thermodynamically unstable systems. Besides the stabilizing efficiency, the criteria influencing the selection of surfactants for pharmaceutical or cosmetic products include safety, odor, color, and purity. 

Pharmaceutical scientists have developed improved suspension dosage forms to overcome problems of poor physical stability and patient-perceived discomfort attributed to some active ingredients. An important development aspect of any suspension is the ability to resuspend easily any settled particles prior to instillation in the eye and ensure that a uniform dose is delivered. It would be ideal to formulate a suspension that does not settle since the patient may not always follow the labeled instructions to shake well before using. However, this is usually not feasible or desirable since the viscosity required to retard settling of the insoluble particles completely would likely be excessive for a liquid eyedrop. The opposite extreme, of allowing complete settling between doses, usually leads to a dense layer of agglomerated particles that are difficult to resuspend. 

The chemical and physical stability of aqueous and nonaqueous suspensions of a number of solvatomorphs of niclosamide has been evaluated in an effort to develop pharmaceutically acceptable suspension formulations [90]. Studied in this work was the anhydrate, two polymorphic monohydrates, the 1 1, Y, A"-dimethyI I ormam ide solvatomorph, the 1 1 dimethyl sulfoxide solvatomorph, the 1 1 methanol solvato-morph, and the 2 1 tetraethylene glycol hemisolvate. All of the solvatomorphs were found to convert initially to one of the polymorphic monohydrates, and over time converted to the more stable monohydrate phase. The various solvatomorphs could be readily desolvated into isomorphic desolvates, but these were unstable and became re-hydrated or re-solvated upon exposure to the appropriate solvent. 

Polymorphism is critically important in the design of new drug API [9] and affects a number of areas. The main impact is to the bioavailability and release profile of a drug substance into the body. This is due to differences in solubility and dissolution rate, between the polymorphs. The chemical and physical stability of the formulated drug substance is also dependent on the polymorphic form. Patented registration of all discovered forms and their manufacturing conditions is an important element in protecting a pharmaceutical companies intellectual property. 

Kendrick BS, Li T, Chang BS. Physical stabilization of proteins in aqueous solution. In Carpenter JF, Manning MC, eds. Rational Design of Stable Protein Formulations Theory and Practice. Pharmaceut Biotechnol 2002 13 61-84. 

Fernando A. Alvearex-Ninez, Leonard, M.R., and Crawford, L.F. Glass transition temperature measurement as predictors of the physical stability of a poorly soluble pharmaceutical agent formulated as solid dispersion. AAPS 2002, Toronto, ON. 

Stability of Liposomes A shelf life of at least two years is requested for pharmaceutical products. Therefore, chemical stability and physical stability are important parameters for the overall performance of liposomal formulations. Additionaly, another very important factor is the retention of encapsulated drug. 

Tingstad reviewed test methods for determining the physical stability of pharmaceutical suspensions. The procedures outlined are designed to determine the state of flocculation of a formulation. Because there is more than one method of preparing stable suspensions, the following test methods and performance criteria were found useful for determining the stability of both flocculated and dispersed systems. 

Knowledge of the physical stability of a formulation is very important for two reasons. First, a pharmaceutical product must look fresh and elegant as long as it remains on the shelf. Second, the active ingredient must be available to the patient throughout the expected shelf life of the product. The causes of deterioration in quality of active ingredient could be due to incompatibility with excipients, oxidation, reduction, hydrolysis, and racemization to name a few. 

Brange J. Physical stability of proteins. In Frokjaer S, Hovgaard L, eds. Pharmaceutical Formulation Development of Peptides and Proteins. London Taylor Francis, 2000 89-112. 

Physical stability is also an issue. Farmers do not have the time to premix individual doses of suspensions, nor constantly shake the bottle between administrations to some several hundred individual cows of their herd. Thus, for example, in the case of suspensions, the final product physical characteristics are often a balance between retardation of sedimentation and ease of flow to draw up into the syringe. Thus a critical evaluation of existing suspension products by a formulation scientist new to the field may draw false conclusions as to the need for an improved product based on ease of administration since there is more than pharmaceutical elegance involved in developing the perfect veterinary formulation. Indeed, a farmer is less interested in what the product looks like compared with its efficacy profile, ease of use, ease of administration, ease of removal, tissue residue profile, and time it takes to herd, administer, and release his animals back into the paddock. Veterinary formulation scientists may therefore trade off pharmaceutical elegance to improve other features, provided the efficacy and safety profile is acceptable and not altered during storage. 

Polymorphic purity of solid drug substances is an important parameter for consideration in pharmaceutical formulation. Since different polymorphs or crystalline forms of the same drug exhibit different physical properties, chemical stability, solubility, dissolution rate, and possibly bioavailability, the presence of the alternative (metastable) crystal form(s) may have an adverse impact on the manufacturing and in vivo performance of the drug product. 

The example of the polymorphs (allotropes) of carbon illustrate the key messages of this chapter different crystal forms of a substance can possess very different properties and behave as different materials. This concept has important implications in all fields of chemistry associated with the production and commercialization of molecules in the form of crystalline materials (drugs, pigments, agrochemicals and food additives, explosives, etc). The producer, in fact, needs to know not only the exact nature of the material in the production and marketing process, but also its stability with time, the variability of its chemical and physical properties as a function of the crystal form, etc. In some areas, e.g. the pharmaceutical industry, the search for and characterization of crystal forms of the API has become a crucial step for the choice of the best form for formulation, production, stability and for intellectual property protection. 

The term stability can have different meanings in the context of protein formulations. A stable pharmaceutical product according to the U.S. Food and Drug Administration definition is one that deteriorates no more than 10% in 2 years [25], Conformational and physical stability of a protein are defined as the ability of the protein to retain its tertiary structure [6], Noncovalent degradation is relevant mainly for proteins having higher order structures, rather than peptides. Native structure is maintained by a balance of noncovalent interactions such as hydrogen bonds, 2005 by CRC Press LLC... 

When formulating any pharmaceutical dosage form, it is important to remember that there is an equilibrium between the bioavailability of the product, its chemical and physical stability and the technical feasibility of producing it. 

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