Preformulation studies

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. 

Process validation is intended to show and document that the process described, when operating within the designated parameters, will produce product of the appropriate quality and demonstrate that the manufacturing process is under full control. Process validation should extend from laboratory-scale and preformulation studies (say to of production scale) to formulation to pilot-scale manufacture (say production scale) to full industrial-scale manufacture, with a clear, logical, and continuous path between these stages. The magnitude of scale-up at each stage should not normally exceed a factor of 10. 

Mass transfer phenomena exist everywhere in nature and are important in the pharmaceutical sciences. We may think of drug synthesis preformulation studies dosage form design and manufacture and drug absorption, distribution, metabolism, and excretion. Mass transfer plays a significant role in each. Mass transfer is referred to as the movement of molecules caused not only by diffusion but also by convection [1],... 

T Durig, AR Fassihi. Preformulation study of moisture effect on the physical stability of pyridoxal hydrochloride. Int J Pharm 77 315-319, 1991. 

The sample temperature is increased in a linear fashion, while the property in question is evaluated on a continuous basis. These methods are used to characterize compound purity, polymorphism, solvation, degradation, and excipient compatibility [41], Thermal analysis methods are normally used to monitor endothermic processes (melting, boiling, sublimation, vaporization, desolvation, solid-solid phase transitions, and chemical degradation) as well as exothermic processes (crystallization and oxidative decomposition). Thermal methods can be extremely useful in preformulation studies, since the carefully planned studies can be used to indicate the existence of possible drug-excipient interactions in a prototype formulation [7]. 

Powder flow is most frequently thought of as relevant to formulation development, and there are numerous references attempting to correlate any one of a number of measures of powder flow to the manufacturing properties of a formulation [34—40]. In particular, the importance of physical properties in affecting powder flow has been well documented. Research into the effect of the mechanical properties on powder flow has, however, been very limited. It is, of course, important to be able to determine and quantitate the powder flow properties of formulations. It is of equal importance, however, to determine the powder flow characteristics of bulk drug early in the development process (preformulation phase). Often, the preformulation or formulation scientist is constrained by time, materials, and manpower. Yet certainly the preformulation studies carried out should be meaningful. Well-defined experimental methods and procedures should be used the information generated should be reproducible and permit useful predictions to be made. 

Thermal methods have found extensive use in the past as part of a program of preformulation studies, since carefully planned work can be used to indicate the existence of possible drug-excipient interactions in a prototype formulation [2], It should be noted, however, that the use of differential scanning calorimetry (DSC) for such work is less in vogue than it used to be. Nevertheless, in appropriately designed applications, thermal methods of analysis can be used to evaluate compound purity,... 

Grunenberg, A., Flenck, J-O., Siesler, FI.W., 1996, Theoretical Derivation and practical Application of Energy / Temperature Diagrams as an Instmment in Preformulation Studies of Polymorphic Drug Substances, International Journal of Pharmaceutics, 129, 147-158. 

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. 

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. 

C. Ahlneck and J.O. Waltersson, Factorial designs in phamaceutical preformulation studies. II. Studies on dmg stability and eompatibility in the solid state. Act. Pharm. Suec., 23 (1986) 139. 

Preformulation studies incorporate API qualification and evaluation of key excipients. Studies should incorporate studies of combinations of API and excipients and a rationale developed for the levels of various excipients chosen. Interactions between the API and excipients are expected and should not form the basis of altering the choice so long as data can be collected to show that the API is available through the shelf-life. 

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. 

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. 

In preformulation studies, the stability and potential formulation issues must be considered before the Lnal salt selection is made. 

Graffner, C., M. E. Johansson, M. Nicklasson, and H. Nyqvist. 1985. Preformulation studies in a drug development program for tablet formulatiodsPharm. Sci74 16-20. 

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. 

During early preformulation studies, capsule formulations are used in Lrst clinical trials. Initially, only a low amount of active substance is used forthe Lrst clinical trials. Subsequently, the dose may be increased to Lnd the optimal therapeutic effect with a minimum of side effects. For this purpose, the amount of drug substance is increased and the amount of Lller, usually lactose, is decreased in the powder mixture that is Llled in hard gelatin capsules (von Orelli and Leuenberger, 2004, ongoing research). 

In order to develop a robust formula for a drug product (pharmaceutical dosage form) it is important to understand the chemical and physical properties of the API in conjunction with excipients that may be used to create the most stable product formula in terms of activity and potency. An outline of possible preformulation studies that should be conducted to ensure a proper and complete understanding of the chemical and physical properties of the API is presented in Table 3. 

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