Compatibility preformulation

It should again be emphasized that at the onset of a new drug program, there are only small amounts of drug substance at hand. One of the first tasks for the preformulation scientist is to establish the framework within which the first clinical batches can be formulated. To this end it is important to know with which common excipients the drug is compatible. Below, the distinction will be made between solid and liquid dosage forms. 

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. 

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]. 

J. I. Wells, Pharmaceutical Preformulation, Excipient Compatibility, Ellis Horwood, Chichester, Chapter 8, 1988. 

H. Leuenberger, W. Becher, A factorial design for compatibility studies in preformulation work, Pharm. Acta Helv., 50 (1975) 88-91. 

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. 

Chrzanowski FA, Ulissi LA, Fegely BJ, Newman AC. Preformulation excipient compatibility testing application of a differential scanning calorimetric method versus a wet granulation simulating, isothermal stress method. Drug Devel Ind Pharm 1986 12(6) 783-800. 

Oxidative instability is the second most common cause of chemical degradation of API in pharmaceutical formulations. If prior knowledge and/or preformulation stability experiments have predicted reactivity toward oxidative degradation, additional oxidative stress conditions can be included into excipient compatibility protocols in several ways. 

In conclusion, drug-excipient compatibility studies have a key role at the early preformulation stages to select excipients or after formulation to help identify the mechanism of any detected instability [14], An understanding of the potential physicochemical interactions of drug with known chemical reactivities of excipients and... 

Moreover, if adequate forced degradation studies (i.e., acid/base hydrolysis) are performed in the early preformulation stage, the identification of a potential degradation product that might arise during excipient compatibility... 

Jacobs, A.L. Determining optimum drug/excipient compatibility through preformulation testing. Pharm. Manuf. 1985, 2 (6), 43. 

Because key excipients are well established in most new product and process development programs, the same degree of preformulation scrutiny is often not required. Compatibility studies with the API, however, should be performed to study possible untoward interactions between the active ingredients and the excipients. It should be kept in mind that small or minor changes in physical and possibly chemical properties upon intimate contact in binary studies with key excipients should not automatically exclude a favored excipient without further critical testing. 

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... 

Determining initial compatibility of the active drug substance with preformulation excipients. 

Preformulation for special or novel drug-delivery systems is basically similar to that of the conventional dosage forms. However, there are some items that may be characteristic of the drug delivery system, such as the drug solubility of a propellant cosolvent mixture, the excipients compatibility with the specific drug delivery system, and stability requirements that are different from those of conventional products. These items deserve additional consideration. 

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