Pharmaceutical development formulation

Cummings PG, Offen P, Olsen MA, Kennedy-Gabb S, Zuber G. LC/MS, LC/ NMR, FTIR an integrated approach to impurity identification in pharmaceutical development formulation. Am Pharm Rev 2003 6(3) 88, 90, 92. 

The first recorded reference to the use of expert systems in pharmaceutical product formulation was in the London Financial Times in the spring of 1989 [3], closely followed by an article in the autumn of the same year [4], Both referred to the work then being undertaken by personnel at ICI Pharmaceuticals, UK (now AstraZeneca) to develop an expert system for formulating pharmaceuticals ab initio. Since that time several companies and academic institutions have reported their experiences. 

Biopharmaceutical issues to be addressed will include a discussion of the pharmaceutical development process as it relates to in vivo and in vitro performance and the general approach taken concerning bioavailability, bioequivalence, and in vitro dissolution profiles. There should be a comparative analysis of relevant studies—objectives, study design, conduct, outcome, and data analyses. The effects of formulation changes (including different strengths of product and... 

In the pharmaceutical industry, surface area is becoming more important in the characterization of materials during development, formulation, and manufacturing. The surface area of a solid material provides information about the void spaces on the surfaces of individual particles or aggregates of particles [5], This becomes important because factors such as chemical activity, adsorption, dissolution, and bioavailability of the drug may depend on the surface on the solid [3,5]. Handling properties of materials, such as flowability of a powder, can also be related to particle size and surface area [4],... 

Evaluation of the dissolution rates of solid drugs is extremely important in the development, formulation, and quality control of solid pharmaceuticals. The... 

Reasons for chopping clinical candidates at any stage of the drug approval process included (1) stability, formulation, or other pharmaceutical development issues, (2) renal toxicity or neurotoxicity, and (3) insufficient advantage over current chugs. Since 1997, the NCI has also operated a screen for compounds active against the cytotoxic effects of HIV in CEM cells. Of 80,000 compounds tested, 4050 (or about 5%) were active. Of the compounds tested, 2291 have included metals. Of those, 136 (about 6%) were active, and two became clinical candidates. Both were chopped due to toxicity problems. One clinical candidate was a polyoxometallate, and therefore about 80 other similar molecules were tested. These were found to be strongly active in vitro, but too toxic in animal models in vivo. If a way around the toxicity problem can be found, interest in these... 

It is estimated that half of all pharmaceuticals are formulated as salts, to achieve increased stability and bioavailability [13]. Predictive solubility methods are very limited for this area, and the development of new models to address this category is very important. The NRTL-SAC model has recently been extended by C.-C. Chen, and Y. Song to represent such electrolytic solutes, that partly dissociate to ions in solution. This extension has been achieved by the addition of one new segment type into the preceding NRTL-SAC model. NRTL-SAC thus becomes a limiting case of the eNRTL-SAC formulation [27]. 

Release-related bioavailability problems have been encountered in the pharmaceutical development of formulations for a number of quite different chemical entities, including ciclos-porin, digoxin, griseofulvin, and itraconazole, to name but a few. A thorough knowledge of hydrodynamics is useful in... 

If a secondary method is required during early phase development, a level 3 method is developed and validated to support phase 2b or early phase 3 clinical studies. This method should be capable of separating all components of interest identified up to this stage of pharmaceutical development. In cases where the initial primary method is still viable, the level 1-level 2 method may be maintained. As in early development, the use of an orthogonal method to evaluate DS generated via new synthetic schemes and to evaluate new formulations remains an important means of assuring that the primary method is sufficient for characterizing DS and DP. 

Pharmaceutical Technology Development Formulation Liquids, F. Hoffmann-La Roche Ltd., Basel, Switzerland... 

In pharmaceutical technology, it is important to develop formulations which are robust to environmental conditions, like temperature changes and relative humidity variation, and that have a long life time. These aspects belong to the quality assurance of pharmaceutical formulations. 

Many stages of new drug development are inherently constrained by time, but the formulation of drugs into desirable dosage forms remains an area where expediency can be practiced by those who have mastered the skills of pharmaceutical formulations. The Handbook of Pharmaceutical Manufacturing Formulations is the first major attempt to consolidate the available knowledge about formulations into a comprehensive and, by nature, rather voluminous presentation. 

Henrar, R.E.C., Kettenes-van den Bosch, J.J., Bult, A., Beijnen, J.H. Pharmaceutical development of a parenteral lyophilized formulation of the novel in-doloquinone antitumor agent E 09. Cancer Chemother. Pharmacol. 34, 416 122,... 

In this chapter, the author s practical experience in developing formulations and manufacturing processes for low-dose pharmaceutical products is shared. To be able to successfully develop a process, it is necessary to pay attention to the details of every step of the whole process including formulation selection, preblending, granulation, and drying. 

According to ICH Guideline Q8 Pharmaceutical Development, the marketing authorization application (MAA) should discuss the excipients chosen and their concentration. The MAA should show the characteristics that can influence the medical product performance and manufacturability relative to the respective function of each excipient. Additionally, the MAA should demonstrate the ability of excipients to provide their intended functionality throughout the intended period of validity of the formulation. Use the information on excipient performance as appropriate to justify the choice and quality attributes of the excipients.26... 

Table 2 lists the most-prescribed anti-inflammatory steroids on the U.S. market today. Table 2 shows that some of the first compounds to be marketed still have a place in the treatment of inflammatory disease 50 years and more after their discovery. Table 2 also illustrates that continued effort to improve potency, to increase safety and to find better drug delivery systems (e.g., inhalers) succeeded in creating marketable products into the 1990s. Today very little, if any, research is going on to find improved steroid anti-inflammatory drugs. Some work continues in the pharmaceutical development area mostly to improve the formulation of existing molecules and to find better delivery systems. 

Abstract The major enzymatic barrier to the absorption of macromolecules, particularly therapeutic peptides, is the pancreatic enzymes the peptidases, nucleases, lipases and esterases that are secreted in considerable quantities into the intestinal lumen and rapidly hydrolyse macromolecules and lipids. In the case of the peptidases, they work in a co-ordinated fashion, whereby the action of the pancreatic enzymes is augmented by those in the brush borders of the intestinal cells. The sloughing-off of mucosal cells into the lumen also furnishes a mixture of enzymes that are a threat to macromolecules. As the specificity and activity of the enzymes are not always predictable, during pharmaceutical development it is important to test the stability of therapeutic macromolecules, and novel macromolecular-containing or lipid-containing formulations, in the presence of mixtures of pancreatic enzymes and bile salts, or in animal intestinal washouts or ideally, aspirates of human intestinal contents. 

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