Bioavailability/dissolution requirements

Early optimism about the possibility of in vitro-in vivo correlation was tempered by the need for a performance test that would yield reproducible results (10). Even though not necessarily correlated to bioavailability, dissolution requirements were seen as useful in controlling variables in formulation or processing. Thus, from the start, sources of variability in the results were seen as factors to be minimized in any proposed compendial method. 

A major reason for the popularity of pharmaceutical co-crystals in industry is that they lend themselves well to patent protection. They admirably satisfy the three criteria of patentability, namely novelty, non-obviousness and utility. A co-crystal almost always satisfies the novelty criterion because it is a new composition of matter. Non-obviousness is provided by the fact that the identification of the co-former is hardly ever routine, unlike say salt formation wherein an acid is obviously required to make a salt from a base. Utility is generally the only criterion that must be established but it is often easy to demonstrate—usually it is the lack of a particular attribute (solubility, bioavailability, dissolution profile, good shelf life) that has led to the identification of a pharmaceutical co-crystal. With respect to patentability, co-erystals offer opportunities vis-d-vis polymorphs. They are clearly new substances, problems of inherent anticipation are not likely to arise so often and more of them can be made for any given API, expanding the pharmaceutical space around it and consequently the types of advantageous properties that may be accessed. 

The information requirements for products such as prolonged-release oral dosage forms will depend on whether or not it has been possible, during the development of the product, to establish an in vivo-in vitro correlation between clinical data and dissolution studies. In vivo-in vitro correlations should be attempted using product at different stages of development, but bioavailability and pharmacokinetics data from pivotal clinical studies using at least pilot-scale production materials and possibly routine production material are particularly important. Where it is not possible to establish an in vivo-in vitro correlation, additional data will be required to compare the bioavailability of product developed at laboratory scale, pilot scale, and production scale. In the absence of an in vivo-in vitro correlation, the dissolution test will be a quality control tool rather than a surrogate marker for in vivo performance of the product. 

The degradation and formation of nonabsorbable drug complexes in the intestinal lumen is the third factor, in addition to dissolution and permeability, which could affect fraction absorption. Limitations of bioavailability due to these factors seem to be less frequent compared with the two other main factors. Regulatory guidelines for BCS-based biowaivers still ask for in vitro studies of luminal degradation in relevant test media, whereas specific binding studies are not required [17]. 

The design of crystallization processes for the manufacture of Active Pharmaceutical Ingredients is a significant technical challenge to Process Research and Development groups throughout the Pharmaceutical and related industries. It requires an understanding of both the thermodynamic and kinetic aspects of crystallization, to ensure that the physical properties of the product will consistently meet specification. Failure to address these issues may lead to production problems associated with crystal size, shape and solubility, and to dissolution and bioavailability effects in the formulated product. 

The Committee for Proprietary Medicinal Products [8] applied the BCS, with certain requirements, to dispense with bioequivalency tests if the active pharmaceutical ingredient is class I and the in vitro dissolution of the finished dosage form is fast [9], An active substance is considered highly soluble if the amount contained in the HDS of an IR product is dissolved in 250 ml of each of three buffers within the range of pH 1-8 at 37°C (e.g., pH 1.0, 4.6, and 6.8). There should be linear and complete absorption, which indicates HP to reduce the possibility of an IR dosage form influencing the bioavailability [8], The similarity of the dissolution profiles of the test and reference products is demonstrated in each of three buffers within the range of pH 1-8 at 37°C (e.g., pH 1.0,4.6, and 6.8). If there is rapid dissolution of the product, where at least 85% of the active substance is dissolved within 15 min, no further comparison of the test and reference is required. Further requirements include that excipients be well established and have no interaction with the pharmacokinetics of the active substance and that the method of manufacture of finished product... 

Nature itself gives us a spectacular example of a biopolymer-based delivery system in the form of the native casein micelle of mammalian milk (Lemay et al, 2007). This is primarily a colloidal delivery system for calcium, where the micronutrient is in the form of calcium phosphate, which does not give a bitter taste, and which provides good bioavailability owing to its colloidal size, amorphous state and quick dissolution in gastric conditions (pH 1-2). Nevertheless, the casein micelle structure is unique there are no other readily available natural delivery systems for most nutraceuticals. Therefore some new designs are clearly required (Velikov and Pelan, 2008 McClements et al, 2008, 2009). 

A 1990 study by Sheikh and Fordlran (Baylor University Medical Center) indicated that there arc important differences in the bioavailabilily of calcium from different calcium-containing compounds. The ability lo dissolve a preparation in dilute acid is a major factor that contributes to bioavailability. Currently, the FDA tFood and Drug Administration. U S.) does not require commercially available products to meet specific dissolution standards. 

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