Preformulation, active

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. 

Development of a Robust Formulation of Low Wettability Drug during Early Preformulation Activities in Relation to Drug Load... 

As part of the preformulation activities, investigations include physiochemical character, purity, solubility, stability, and optimal pH studies. In preparation for clinical studies, potential product formulations considering route of administration and solution stability are also studied. Unique to dosage form development studies for lyophilized products, thermal analysis of the drug substance and product formulations are also necessary. Data generated during this phase of product development is useful for future development activities, along with validation. 

A reliable analytical method must be available before preformulation studies are started and hence method development activities must precede preformulation activities. The analytical method should be capable of separating the active and any major degradation product(s) and thus be stability-indicating. Analytical methods such as titration and ultraviolet (UV) spectroscopy are not used since they are not considered to be stability-indicating. Only HPLC has been widely used as the method of choice in recent years because of its efficiency, applicability for a wide range of chemical compounds, and ease of... 

The International Conference on Harmonization (ICH) guidelines regarding the quality of drug substances are specific and require frequent referral to keep the preformulation activities current with the regulatory requirements. The pertinent guidelines are listed in the following. 

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). 

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. 

Lin, S.-L., L. Lachman, C. J. Swarz, and C. F. Huebner. 1972. Preformulation investigation. I. Relation of salt forms and biological activity of an experimental antihypertensilvEharm. Sci61 1418-1422. 

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). 

Preformulation profde or characterization of the components of the formula, which includes all the basic physical or chemical information about the active pharmaceutical ingredients (API, or the chemical entity) and excipients... 

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. 

The formulation, manufacturing process, analytical development, and long-term toxicology studies in animals are parallel to the clinical investigation (Table 1.1). Clinical trial materials should be developed, manufactured, tested, and released before conducting a phase I clinical trial. Process chemists may redesign the synthetic route for the dmg candidate to meet the requirements of large-scale production in a pilot plant. Preformulation scientists complete the activities of salt selection,... 

Hence it is important to study this effect during preformulation by testing the solubility of the salt in the presence and absence of sodium chloride. Although salts do not alter the pharmacological activity of the drug, safety is an important consideration in the selection of salts. From this perspective, salts are treated as a new molecule by the FDA. The safety of the salt is evaluated with respect to its route of administration and dose of the drug [37],... 

By the time an active pharmaceutical ingredient (API) is made available to an analytical chemist in the formulation development group, most or all of the physical characteristics of an API has already been studied and the information should be available in some sort of a report from the drug substance group or preformulation group. Some of the key parameters that an analytical chemist in formulation development requires from such a report are the solubility and solution stability. 

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. 

Personnel at the Sanofi Research Division of Philadelphia recently developed an expert system for the formulation of hard gelatin capsules based on specific preformulation data of the active ingredient. Using Formulogic, the system generates one first-pass clinical capsule formulation with as many subsequent... 

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