Formulations dosage variations

Implantable formulations of estrogens have been reviewed (221). Subcutaneous implants have as a rule durations of action of 4-12 months, depending on the dosage and formulation used variations can be due to technical problems, such as disintegration or migration of an implant. 

Comprehensive physicochemical characterization of any raw material is a crucial and multi-phased requirement for the selection and validation of that matter as a constituent of a product or part of the product development process (Morris et al., 1998). Such demand is especially important in the pharmaceutical industry because of the presence of several compounds assembled in a formulation, such as active substances and excipients, which highlights the importance of compatibility among them. Besides, variations in raw materials due to different sources, periods of extraction and various environmental factors may lead to failures in production and/or in the dosage form performance (Morris et al., 1998). Additionally, economic issues are also related to the need for investigating the physicochemical characteristics of raw materials since those features may determine the most adequate and low-cost material for specific procedures and dosage forms. 

As the list of applications illustrates, the techniques of optimization are not limited to tablets or even to solids. Any dosage form and any process should be amenable to this type of experimentation and analysis. From the most simple formulation to the most complicated one, there are ingredient levels and processing steps that can be varied, and any information on the result of such variation should be useful to the formulator. 

It is evident even to the casual observer that the vast majority of pharmaceutical products are administered as solid dosage forms, which are in turn produced by the formulation and processing of powdered solids. All too often characterization of raw materials and products has centered on aspects of chemical purity, with only passing attention being given to the physical properties of the solids. However, every pharmaceutical scientist knows of at least one instance in which a crisis arose due to some variation in the physical properties of input materials, and in which better characterization would have prevented the problem. 

Frequently, the formulation used in clinical trials is not the one that is ultimately marketed. The pharmaceutical dossier is scrutinised for these variations and to ensure that studies have been carried out to prove the bioequivalence of the two. The same applies if more than one dose strength or dosage form is to be marketed, for example, tablets for adults and liquid preparations for use in children. 

Overdosage and underdosage relative to the prescribed dosage—both aspects of failure of compliance—can frequently be detected by concentration measurements when gross deviations from expected values are obtained. If compliance is found to be adequate, absorption abnormalities in the small bowel may be the cause of abnormally low concentrations. Variations in the extent of bioavailability are rarely caused by irregularities in the manufacture of the particular drug formulation. More commonly, variations in bioavailability are due to metabolism during absorption. 

It is reasonable to use proprietary names when dosage, and therefore pharmaceutical bioavadability, are critical so that small variations in the amoimt of drug available for absorption can have big effects on the patient, e.g. drugs with low therapeutic ratio, digoxin, hormone replacement therapy, adrenocortical steroids (oral), antiepileptics, cardiac anti-arrhythmics, warfarin. Also, with the introduction of complex formulations, e.g. sustained-release, it is important clearly to identify these, and use of proprietary names has a role. 

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