Physicochemical and biopharmaceutical properties

The parallel screening of drug candidates for their pharmacological activity and for their physicochemical and biopharmaceutical properties has become a major challenge in dmg development and is performed at very early stages... 

The dosage-form design is guided by the properties of the drug candidate. If an NCE does not have suitable physical and chemical properties or pharmacokinetic attributes, the development of a dosage form (product) may be difficult and may sometimes be even impossible. Any heroic measures to resolve issues related to physicochemical and biopharmaceutical properties of drug candidates add to the time and cost of drug... 

Thermoresponsive acrylamide co-polymers were also used to alter the physicochemical and biopharmaceutical properties of avidin. Similar to PEG, the acrylamide co-polymers with a lower critical solution temperature (LCST) of about 37 °C were conjugated to the protein amino groups. The polymers were conjugated either by polymer multipoint attachment using polyfunctional polymers or by single chain attachment using end-chain monoactivated polymer. In both cases, the polymer conjugation was found to produce bioactive derivatives with reversible thermal character (Fig. 11.12). 

Lead compounds that survive the initial screening are then optimized or altered to improve their drugability and developability (that is, they are developed to achieve better physicochemical and biopharmaceutical properties and more effective and safer profiles in animals). Scientists make and laboratory-test hundreds of different variations or analogs of the initial lead compounds to evaluate the structure-activity relationship (SAR) of the hits. 

Pharmaceutical excipients available on the market seem sufficient to support typical oral solid dosage form development. In some cases, new chug candidates have physicochemical and biopharmaceutical properties that are less than ideal. These chugs present formulation challenges and may require either the discovery of new excipients or improvement of existing excipients. From a regulatory perspective, there is no answer for the question of registration of an excipient as a separate entity. 

Drug Properties. In keeping with the QbD concept, the physicochemical and biopharmaceutical properties of drug substance should be characterized for a better... 

A rational approach to dosage form design requires a complete understanding of the physicochemical and biopharmaceutical properties of the drug substance. For example, the successful design of an efficacious oral dosage form requires an understanding of the... 

The physicochemical and biopharmaceutical properties of the drug can have a tremendous impact on its bioavailability and, hence, on its efficacy and toxicity profile. Thus, understanding these parameters is often tantamount to the selection and development of the optimum dosage form. 

Once the physicochemical and biopharmaceutical properties of the drug are determined and the desired plasma concentration profile is defined, the pharmaceutical scientist can select and develop an efficacious dosage form by utilizing a formulation approach, a prodrug approach, a device approach, or an alternative administration route approach. 

The selection of a salt form directly influences the physicochemical and biopharmaceutical properties of a compound. The impact of salt selection has been reviewed. Nelson examined the dissolution of theophylline salts and commented on their impact on oral administration. The dissolution rates of the theophylline salts proceeded independently of the pH of the medium but was governed by the diffusion layer pH. The choline and isopropanolamine salts dissolved three to four times faster than the ethylenediamine salt and produced higher and prolonged blood levels. 

Physicochemical and Biopharmaceutical Properties of Drug Substances and Pharmacokinetics... 

P. Caliceti, O. Schiavon, T. Hirano, S. Ohashi, EM. Veronese, Modification of physicochemical and biopharmaceutical properties of superoxide dismutcise by the conjugation to the copolymer of divinyl ether and maleic anhydride, /. Control. Release, 39,27-34,1996. 

The physicochemical and other properties of any newly identified drug must be extensively characterized prior to its entry into clinical trials. As the vast bulk of biopharmaceuticals are proteins, a summary overview of the approach taken to initial characterization of these biomolecules is presented. A prerequisite to such characterization is initial purification of the protein. Purification to homogeneity usually requires a combination of three or more high-resolution chromatographic steps (Chapter 6). The purification protocol is designed carefully, as it usually forms the basis of subsequent pilot- and process-scale purification systems. The purified product is then subjected to a battery of tests that aim to characterize it fully. Moreover, once these characteristics have been defined, they form the basis of many of the QC identity tests routinely performed on the product during its subsequent commercial manufacture. As these identity tests are discussed in detail in Chapter 7, only an abbreviated overview is presented here, in the form of Figure 4.5. 

In the last forty years, the conjugation of methoxy-poly(ethylene glycol) (mPEG) has evolved to become a well-estabhshed technology for the improvement of the physicochemical and therapeutic properties of biopharmaceutical peptides and proteins (PEGylation). In fact, eleven PEGylated products are available nowadays in the marketplace, while several others are under clinical evaluation. 

Equations (1.4) and (1.5) were written intentionally in these two forms to indicate that Kand tll2 are functions of Cl and Vd, and not vice versa. The anatomy and physiology of the body, along with the physicochemical properties of the drug, combine to form the biopharmaceutical properties, such as Cl and Vd, which can be found in many reference books.25... 

Depending on the structure of the organization, the contents of the preformulation report may be included in several different reports. Typically, the analytical profile may be issued by the analytical development group, and specifications of the drug substance may be issued by the QC laboratory. Physicochemical property determination, stability, compactibility, and pharmaceutical properties may be reported by the basic pharmaceutics or physical pharmacy group. The biopharmaceutical group may issue the report with KADME and bioavailability data. 

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