Testing preformulation studies

Preformulation testing of the specific API of interest and key excipients to be used in the product design stage, alone and in combinations with the API, should be included as a preliminary first step in the product and process development sequence. A simple check list of items worth consideration in preformulation studies with APIs and important or critical excipients is provided as follows ... 

To establish quality assurance, control of dosage forms, starting from clinical trial to production for market introduction, must be imposed on in-process operations and product testing for compliance with the specifications and guidelines of quality operation to ensure product attributes. Occasionally, specifications may be revised because of new evidence discovered in the continuous preformulation study. 

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. 

Raman spectroscopy is a nondestructive tool and requires little or no sample preparation. A sample may be analyzed in solid or powder form or in an aqueous solution and placed in glass containers such as an NMR tube, GC vial, test tube, light-path cell, or glass bottle. Aside from structure elucidation and functional group analysis, FT-Raman may be used for quantitative determination of polymorphs in a preformulation study. 

Over the last 20 years, separation technology for analytical testing in the pharmaceutical industry has undergone great advances. This progress was motivated by the need for better quality products, the desire for improved knowledge in product development, and, in part, regulatory requirements. Separation techniques such as TLC, HPLC, GC, LC, counter current extraction (CCE), and capillary electrophoresis (CE) are extensively employed in preformulation studies. 

One of the major factors that often slows down preformulation studies is the availability of a sufficient quantity of a compound at this stage, especially if biopharmaceutic studies are conducted as a result, methods need to be devised that would utilize the smallest quantity of the substance this is amply emphasized throughout the testing phases in this book. Another factor that often slows down work at this stage is often misplaced importance on validated test methods and documentation while this is desired, the perennial shortage of manpower requires that some things take secondary importance. 

At the early stages of optimisation, preformulation studies are usually conducted to screen excipients or packaging materials and to select those compatible with the candidate drug, using accelerated stress testing procedures. More details about the preformulation techniques, which can be employed for compatibility studies, are discussed in Chapter 3. The importance of doing compatibility studies is for reducing the number of excipients and formulation options to test in further product optimisation studies. 

---