Solvents preformulation studies

Methods for concentrating proteins include membrane filtration, osmotic removal of solvent, and solvent evaporation (reviewed by Shire et al., 2004). Early in preformulation studies when material is limited, small-scale methods... 

Hydrates and solvates can be prepared by crystallization in water or an organic solvent or by conversion of the anhydrous material through moisture or solvent adsorption. In quality control testing, hydrates or solvates are identified by the assay of water of crystallization or solvent found in the crystal. Water determination is achieved by Karl Fischer titration or a coulometric method or loss-on-drying by the USP method. In the preformulation study, the hot stage microscope is a useful simple technique. TGA can also be an informative tool, as shown in Figure 15. 

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. 

One approach to the study of solubility is to evaluate the time dependence of the solubilization process, such as is conducted in the dissolution testing of dosage forms [70], In this work, the amount of drug substance that becomes dissolved per unit time under standard conditions is followed. Within the accepted model for pharmaceutical dissolution, the rate-limiting step is the transport of solute away from the interfacial layer at the dissolving solid into the bulk solution. To measure the intrinsic dissolution rate of a drug, the compound is normally compressed into a special die to a condition of zero porosity. The system is immersed into the solvent reservoir, and the concentration monitored as a function of time. Use of this procedure yields a dissolution rate parameter that is intrinsic to the compound under study and that is considered an important parameter in the preformulation process. A critical evaluation of the intrinsic dissolution methodology and interpretation is available [71]. 

Solubility is highly influenced by the solid-state form (e.g., crystalline or amorphous) of the drug. Rigorous solubility studies using the final solid form (i.e., salt form or crystal form) as a function of temperature (i.e., 25 and 37°C) and pH (range 1 to 7.5) are conducted during preformulation. Solubility in nonaqueous solvents is also screened. Solubility in simulated gastrointestinal fluids is also important. 

Drug solubility is one of the physicochemical parameters that receives lots of attention during preformulation testing. In the initial stages, solubility studies are usually kinetically determined, where the drug is placed in contact with the solvents and then the solubility is assessed using turbidometric methods almost instantaneously. 

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