Preformulation stage

The therapeutically active dmg can be extracted from plant or animal tissue, or be a product of fermentation (qv), as in the case of antibiotics. Frequentiy, it is synthesized and designed to correlate stmcture with therapeutic activity. Pharmacologic activity is first tested on laboratory animals. When the results ate encouraging, physical and chemical properties are determined in the so-called preformulation stage, and analytical procedures are developed for quahty control (see Qualityassurance/qualitycontrol). 

During the preformulation stage, the chemical and physical properties of the dmg moiety are studied exhaustively to ensure stabdity, safety, bioavadabdity, and therapeutic efficacy. Tablets are produced directly by compression of powder blends or granulations, which include a small percentage of fine, particle-sized powders. 

If a compound exhibits polymorphism, one of the forms will be more stable (physically) than the other forms that is, of n existing forms n -1 forms will possess thermodynamic tendency to convert to the nth, stable form (which then has the lowest Gibbs energy it should be noted that in the preformulation stage it is not known whether the form on hand is the stable polymorph or not). 

Liquid paraffins, particularly those of low viscosity, have been used and are said to be of value for colored tablets, and even the use of modified vegetables has been attempted. However, they appear, in general, to offer little advantage over solid lubricants, and their incorporation into the precompression mixture is more difficult, requiring solution in a volatile liquid that is then sprayed onto the unlubricated material. Due to handling and EPA requirements, these materials are often rejected in the preformulation stage. 

Since an understanding of the nature of water sorption by materials is of extreme interest to the formulator, an evaluation of the degree of hygroscopicity associated with a given material is crucial to the development process. A systematic approach for these types of studies has been outlined, in which the kinetics of water adsorption can be deduced [84]. This work should be performed at the preformulation stage, where the effect of water on the various components (and mixtures of these) needs to be addressed prior to any final decision as to the formulation composition [85]. It would be far better to discover any... 

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... 

Polymorphism is an ability of the drug substance to form crystals with different molecular arrangements giving distinct crystal species with different physical properties such as solubility, hygroscopicity, compressibility, and others. This phenomenon is well known within pharmaceutical companies. The reader can find additional information in references 47 and 48. The determination of possible polymorphic transition and existence of thermodynamically unstable forms during preformulation stage of drug development is important. Typical methods used for solid-state characterization of polymorphism are DSC,... 

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... 

The first stage of formulation development is called preformulation. During the preformulation stage, short studies are conducted to assess the relative types and rates of degradation observed as a function of pH, protein concentration, and temperature. It is from these early studies that the formulation scientist first gains information regarding which specific degradation mechanisms may be important to the protein of interest. 

The properties that are to be evaluated for the API during the preformulation stage include the following ... 

Solution dosage forms offer several advantages, particularly the resolution of bioavailability problems, instant administration as injectable forms (though nonsolution forms are also given parenterally). At the preformulation stage, more important factors are the solubility (and any pH dependence) and stability of the new compound. 

In a review of milling, it was stated that ball milling was the most commonly used type of tumbling mill in pharmacy (Parrot 1974). Indeed, it is probably used most often at the preformulation stage to reduce the particle size of small amounts of a compound, especially for the preparation formulations to be administered to animals. At the lead optimization (LO) stage, however, only small quantities (e.g., 50 mg) will be available to administer to a test animal. For a review of high purity applications of ball milling, such as pharmaceuticals, see Vernon (1994). 

Data considered to be important for suspensions at the preformulation stage include solubility, particle size and propensity for crystal growth and chemical stability. Furthermore, during development, it will be important to have knowledge of the viscosity of the vehicle to obtain information with respect to settling of the suspended particles, syringibility and physical stability (Akers et al. 1987). In a report on the preformulation information required for suspensions, Morefield et al. (1987) investigated the relationship between the critical volume fraction as a function of pH. They noted that it is usually desirable to maximize the volume fraction of solids in order to minimize the volume of the dose . 

One way in which the transport of zwitterionic drugs through skin has been enhanced is by salt formation. This was demonstrated by Mazzenga et al. (1992) who showed that the rank order of epidermal flux of the salts of phenylalanine across the epidermis was hydrobromide > hydrochloride > hydrofluoride > phenylalanine. Thus, like most other delivery routes, it is worth considering salt selection issues at the preformulation stage to optimize the delivery of the compound via the skin. 

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