Solubility preformulation studies

Serajuddin, A.T.M., Sheen, P.C., Mufson, D., Bernstein, D.F., and Augustine, M.A., Preformulation study of a poorly water soluble drug, alpha-pentyl-3-(2-quinolinyl-methoxy) benzenemethanol selection of the base for dosage form design, /. Pharm. Sci., 75, 492, 1986. 

Shah JC, Chen JR, Chow D. Preformulation study of etoposide. 2. Increased solubility and dissolution rate by solid-solid dispersions. Int J Pharm 1995 113 103-111. 

Serajuddin, A. T. M., P. C. Sheen, and M. A. Augustine. 1986. Preformulation study of a poorly water-soluble drugp<-pentyl-3-(2-quinolinylmethoxy) benzenemethanol Selection of base for dosage form design.J Pharm Sci75 492-496. 

Drugs may also have more than two pKa values, such as polyprotic or polybasic compounds (e.g., minocycline), and such drugs exhibit a complex pH solubility profile. It is essential to know per se pH of the drug solution during preformulation studies. The pH is measured or theoretically calculated if the pKa and drug concentration C are known. The pH of a weak acid or the salt of a weak base and a strong acid can be calculated using the equation... 

Characteristics of the product and functions in early clinical studies are the driving force for initial product development. Often, there is a nominal knowledge of the API characteristics at such an early juncture. Preformulation studies provide attributes such as solubility, effects of pH, and predict sensitivities to environmental conditions. Solubility, along with pharmacologic characteristics, dictates the volume in the product container. Sensitivities to environmental conditions include temperature, light, oxygen, and contact surfaces. Specific to lyophilized preparations, there is also the potential for degradation via hydrolysis reactions when in the presence of water. Each of these... 

The measurement of IDR forms an important part of preformulation studies as they permit direct solubility and dissolution rate comparisons between different drug candidates, salts, polymorphic and pseudopolymorphic forms. The measurements are relatively straightforward to carry out but require a minimum of about 200mg of sample per determination. Production of the pellet can occasionally result in a pressure-induced polymorphism change the new polymorph may have different dissolution properties. Therefore, the presence or absence of a new polymorph should be verified by IR spectroscopy or by Differential Scanning Calorimetry (DSC). 

Quantitative determination of a single drug substance in a nonchromo-phoric solvent such as an aqueous or alcohol solution may be a good application for the UV method. In a preformulation study, solubility, dissolution rate, and some stability studies (when degradation products have a different absorption maximum from the parent compound) are performed with the UV technique. UV is extensively used for HPLC detection. 

Preformulation studies inevitably extend beyond the basic characterization of the lead compound, because what is considered as an acceptable characteristic of a lead compotmd will largely depend on the intended or anticipated dosage form. For example, the solubility issues will largely determine the route of administration conversely, if a particular route of administration is the only desired route, then preformulation studies should attempt to find out the structural changes necessary for the candidate molecule. 

Early preformulation studies are often performed to obtain initial information regarding drug absorption but may be restricted by solubility problems of the active drug. During early... 

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