Screening preformulation studies

In a more traditional pharmaceutical setting, this characterization would be done during preformulation studies. With the availability of automation and the ability to conduct most of these experiments with small quantities of material, more preformulation activities are being shifted earlier into drug discovery. Recently, Balbach and Korn37 reported a "100 mg approach" to pharmaceutical evaluation of early development compounds. Additional absorption, metabolism, distribution, elimination, and toxicity38 screens may also be conducted at this stage. 

Tong, W.Q. and Whitesell, G. (1998l)n situ salt screening useful technique for discovery support and preformulation studie harm. Dev. Tech., 3, 215-223. 

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. 

Product quality can be compromised during manufacture, transport, storage or use. The causes of deterioration can be manifold and product-specific. They include microbial spoilage or chemical transformation of the active or physical changes that alter performance in vivo. Deterioration can compromise safety or make the medication less attractive, which means it may not be used. Excipients can contribute to or cause such changes unless carefully screened for possible interactions in preformulation studies. 

Tong, W. Q., Whitesell, G. In situ salt screening — a useful technique for discovery support and preformulation studies. Pharm. Dev. Technol 1998, 3(2), 215-232. 

To comply with the concept that in preformulation studies minimal amounts of compound are used, an in situ salt screening technique for basic compounds has been developed by Tong and Whitesell (1998). The steps involved in this process are listed below ... 

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. 

The problem of preformulation studies for screening of excipients to know their compatibility with the drug substance, given in table 2.8, is here simplified by reducing the number of possibilities in each class of excipient (factor) to 2 (9). For this illustration we will also eliminate the final variable, the presence or not of a gelatine capsule shell. The excipients tested and their concentrations are therefore those of table 2.10. 

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. 

Excipient compatibility studies are an important part of any preformulation screen for a new API. However, it is important to remember that an excipient compatibility screen can only indicate the excipients to be avoided because of an obvious chemical incompatibility. The results from excipient compatibility studies are not always easy to interpret, particularly if a physical interaction is found. As stated above, physical interactions can be detected using some form of calorimetry in conjunction with, e.g., chromatography, but the interpretation of the significance of the interaction probably requires prior experience of the excipient and its interactions. It is difficult to predict that the molecular structure of the excipient will interact physically with the chemical structure of the API molecule. 

Methods to Study the Solid State during Preformulation Screening. 535... 

Equally important in screening initial preformulations is the selection of a rubber stopper compatible with protein solutions. The variety of composition of mbber stoppers in parenteral formulations of biopharmaceuticals requires studies on compatibility with proteins, involving chemical extractants from the rubber composition into the protein solution over periods of stability at varying temperatures. We must also consider particle shedding from the stoppers into the protein solution, adsorption, absorption, permeation through the... 

Preformulation screening of the antioxidant efficiency in parenteral solutions containing epinephrine has been reported by Akers (1979), who concluded that screening was difficult on the basis of the redox potential, and was complicated by a complex formulation of many components. Indeed, the most recent study on the preformulation screening of antioxidants found that the ability of an antioxidant to consume the oxygen in the formulation was a superior indicator of suitability when compared to redox methods (Ugwu and Apte 1999). 

Validation can be considered to start with the conception of the formulation. Thus the presence of each component may be justified as a result of the experimental designs, carried out at the preformulation and formulation stages of the project, such as the screening and compatibility testing described in chapter 2. The quantitative composition is supported by the response surface and optimization studies carried out according to the methods of this and the previous chapter and, more specifically, for mixtures in chapters 9 and 10. 

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