Stability studies preformulation

The compatibility of the active ingredient with other active ingredients and excipients should be demonstrated. Preformulation study reports often provide useful relevant information. Preliminary stability study reports may be used as supporting data. 

Hirsh CA, Messenger RJ, Braimon JL. Fenoprofen drug form selection and preformulation stability studies. / Pharm Sci 1978 67 231-6. 

J.O. Waltersson, Factorial designs in pharmaceutical preformulation studies. I. Evaluation of the application of factorial designs to a stability study of dmgs in suspension form. Act. Pharm. Suec., 23 (1986) 129. 

T eraoka R, Matsuda Y. Stabilization-oriented preformulation study of photo labile mena-tetrenone (vitamin K2). Int J Pharm 1993 93 85-90. 

With the results of the preformulation studies, the formulation scientist can begin to address some of the specific questions pertaining to the development of the final formulation. The state of the dosage form is selected. The inactive ingredients in the formulation, excipients, which promote stability of the final product, are screened. Finally, supportive accelerated stability studies are conducted to aid in the selection of the final formulation. 

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. 

TGA may be used to determine moisture content related to weight loss in isothermal or nonisothermal stability studies. In the preformulation study, differentiation of polymorph from hydrate or identification of monohydrate from among other hydrates by DSC alone may not be possible. TGA is the appropriate technique for this purpose. 

Additional preformulation and physicochemical characterization of the candidate compound are performed and stress stability studies may be initiated. Ideally, the optimal solid state (polymorphic) and chemical (salt) form of the molecule are identified as part of clinical candidate selection. Selection of the most stable and bioavailable form will expedite subsequent development. The methods for testing the drug substance are refined and additional methods may be developed. 

CA Hirsch, RJ Messenger, JL Brannon. Fenoprofen Drug form selection and preformulation stability studies. J Pharm Sci 67(2) 231, 1978. 

At the completion of product optimisation, when the best product variant has been selected, it is a good idea to summarise the work conducted in a Product Optimisation Report. The report should reference the primary data from preformulation, product optimisation and stability studies, cross-referencing other investigational reports where necessary. It should clearly justify the recommendations for the quantitative formula and the excipient, component and product specifications. Such a document can be very useful to aid smooth technology transfer into production and for writing regulatory submissions. 

The FDA may also want to audit R D to gain assurance that the product development has been done satisfactorily. In particular, the FDA may wish to see data that support the manufacturing process and controls from preformulation, product/process optimisation, clinical trials process validation and stability studies. 

The first step in development of the dosage form is preformulation to determine the major degradation pathway and to understand the mechanism of degradation. Oftentimes, the degradation pathway is dependent on the type of stress that is applied (e.g., thermal, light, moisture), and hence, the stress degradation studies may not be predictive of the real-time stability studies. To date, all the commercial mAb formulations are either lyophilized or liquid formulations that are intended to be stored at 2 to 8°C (refrigerated) condition (refer to Table 26.1). 

R. Teraoka and Y. Matsuda, Stabilization-oriented preformulation study of photolabile menatetrenone (vitamin K2), lnt. J. Pharm. 93, 85-90(1993). 

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