Preformulation

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. 

Although only the types of surfactants presently used in main detergent formulation have been indicated, the system allows for processing of a wider range of product while still complying with the maintenance of the quality level of the feed. Moreover, products like hydrotropes or blends of surfactants and inorganic salts can be conveniently processed to yield preformulated surfactant bases ready for incorporation in formulated detergents. 

A prototype system implemented with the Formulogic shell has recently been reported by Pfizer [21]. The system has been designed to use preformulation data on new drugs and recommend early development formulations, predict product properties, and select processing conditions suitable for scale-up. 

The system developed by personnel at Sanofl uses the Formulogic shell with specific preformulation data on the drug. The system recommends one first-pass clinical capsule formulation with as many subsequent formulations as desired to accommodate an experimental design [24]. An example of a formulation proposed for naproxen at a dose of 500 mg is shown in Table 28.2. In addition to the formulation the system provides advice on the milling of the drug, the process to be used for blending, and details of the capsule shell. 

Ramani KV, Patel MR, Patel SK. An expert system for drug preformulation in a pharmaceutical company. Interfaces 1992 22 101-8. 

Wells, J. I. Pharmaceutical Preformulation, Ellis Horwood, London, 1988. 

The latter adverb implies that some of the physical chemistry had to be known, and this necessitated determination of physicochemical properties, a fact that is also part of preformulation. The approach was so logical, indeed, that it eventually became part of official requirements for INDs and NDAs [1] ... 

Sufficient quantity is synthesized to (a) perform initial toxicity studies, (b) do initial analytical work, and (c) do initial preformulation. 

For hydrophobic, (virtually) nonionizable substances [i.e., those that show no ionic species of significance in the pH range 1 to 10 (e.g., diazepam)], solubility can usually be improved by addition of nonpolar solvents. Aside from solubility, stability is also affected by solvents in either a favorable or a nonfavorable direction [6], Theoretical equations for solubility in water [7] and in binary solvents [8] have been reported in literature, but in general the approach in preformulation is pseudoempirical. Most often the solubility changes as the concentration of nonpolar solvent C2, increases. For binary systems it may simply be a monotonely changing function [9], as shown in Fig. 2. The solubility is usually tied to the dielectric constant, and in a case such as that shown by the squares, the solubility is often log-linear when plotted as a function of inverse dielectric constant, E, that is,... 

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). 

One manner in which different polymorphs are created is by way of recrystallizing them from different solvents, and at a point in time when sufficient material (and this need not be very much) is available, the preformulation scientist should undertake recrystallization from a series of solvents. 

Knowledge of polymorphic forms is of importance in preformulation because suspension systems should never be made with a metastable form (i.e., a form other than the stable crystal form). Conversely, a metastable form is more soluble than a stable modification, and this can be of advantage in dissolution [Eq. (9)]. There are two types of polymorphism, a fact illustrated in the following discussion. 

Partition coefficients between water and an alkanol (e.g., octanol) should be determined in preformulation programs [26]. The partition coefficient of a compound that exists as a monomer in two solvents is given by... 

In general, vapor pressures are not all that important in preformulation, but it should always be kept in mind that a substance may have sufficiently high vapor pressure to (a) become lost to a sufficient extent to cause apparent stability problems and content uniformity problems and (b) exhibit a potential for interaction with other compounds and adsorption onto or sorption into package components [27],... 

Moisture isotherms were, up until recently, not considered part of preformulation. However, with the advent of microcalorimetry, moisture isotherms and surface areas may be determined with mg quantities of drug substance [29,30]. 

The size of particles is of great importance, and particle size determinations should be carried out in preformulation as well in formulation functions. For small particle sizes, simple microscopy [41] may be used, but again imaging techniques, particularly with motorized stages, are more representative and much easier to carry out [42],... 

The experiments above are rather easy to carry out and should always be part of a preformulation program, since hygroscopicity can be so important that it will dictate whether or not a particular salt should be used. Dalmane, for instance, is a monosulfate and is used as such since the disulfate, desirable in many other respects, is so hygroscopic that it will remove water from a hard-shell capsule and make it exceedingly brittle. 

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. 

In preformulation one task is to establish the stability of the drug substance in both solid and dissolved state. In the latter case it is important, with small samples of drug substance, to assess (a) the effect of buffer type, (b) the effect of buffer concentration, (c) the effect of pH in a practical range, (d) the effect of temperature, and (e) the kinetic salt effect. 

The horizontal part is due to the uncatalyzed rate constant, k+, in Eq. (43). A pH profile can be done at, for example, six pH values, and since there are two kinetic points (times) and two buffer concentrations at each, a total of 24 assays are needed, which is not insurmountable. This number may be minimized and optimized by careful selection of pH and buffer concentrations [60]. Later in the program the pH profile should be repeated but with multiple points and several buffer concentrations, but this is beyond the point of preformulation. An example of a full pH profile is one running from pH 1 to pH 11 [61-64]. 

---