Active pharmaceutical ingredient bioavailability

The design of crystallization processes for the manufacture of Active Pharmaceutical Ingredients is a significant technical challenge to Process Research and Development groups throughout the Pharmaceutical and related industries. It requires an understanding of both the thermodynamic and kinetic aspects of crystallization, to ensure that the physical properties of the product will consistently meet specification. Failure to address these issues may lead to production problems associated with crystal size, shape and solubility, and to dissolution and bioavailability effects in the formulated product. 

The Committee for Proprietary Medicinal Products [8] applied the BCS, with certain requirements, to dispense with bioequivalency tests if the active pharmaceutical ingredient is class I and the in vitro dissolution of the finished dosage form is fast [9], An active substance is considered highly soluble if the amount contained in the HDS of an IR product is dissolved in 250 ml of each of three buffers within the range of pH 1-8 at 37°C (e.g., pH 1.0, 4.6, and 6.8). There should be linear and complete absorption, which indicates HP to reduce the possibility of an IR dosage form influencing the bioavailability [8], The similarity of the dissolution profiles of the test and reference products is demonstrated in each of three buffers within the range of pH 1-8 at 37°C (e.g., pH 1.0,4.6, and 6.8). If there is rapid dissolution of the product, where at least 85% of the active substance is dissolved within 15 min, no further comparison of the test and reference is required. Further requirements include that excipients be well established and have no interaction with the pharmacokinetics of the active substance and that the method of manufacture of finished product... 

For pharmaceutical scientists, the value in cocrystals would be if such materials would be superior active pharmaceutical ingredients relative to the drug substance itself. This possibility has been studied for the carbamazepine-saccharin cocrystal, where its performance characteristics were compared with the marketed form of carbamazepine [46]. It was learned that the physical and chemical stability of formulations containing the carbamazepine-saccharin cocrystal product were similar to those of carbamazepine in the marketed product, and comparative bioavailability studies demonstrated that the cocrystal was a viable alternative drug substance to the anhydrous drug form used in the conventional solid dose forms. 

Formulation design is based on the physical, chemical, and biopharmaceutical properties of a drug substance. A formulation for direct compression is composed of active pharmaceutical ingredients and other inactive ingredients such as fillers, binders, dis-integrants, flow aids, and lubricants. Simplicity is the basis of good formulation design. Minimally, a direct compression tablet formulation must meet requirements for manufacturability, uniformity of dose, physical and chemical stability, appropriate dmg release profiles, and bioavailability. In addition, the formulation must meet many quality standards and special requirements to ensure the efficacy and safety of the product. 

In addition to active pharmaceutical ingredients excipients used for the manufacture of finished drugs have - sometimes essential - influence on the therapeutic value of a drug. They may, e. g., be a contributory determinant of bioavailability and shelf-life. 

In the pharmaceutical industry, the issue of better control, desirable in itself, is reinforced by the need to assure the regulatory authorities that a continuing supply of active pharmaceutical ingredients (APIs) of high and reproducible quality and bioavailability can be delivered for formulation and finally to the patient. The product image (properties, purity, etc.) of this medicine must be the same as that used in the clinical testing carried out to prove the product s place in the therapeutic marketplace. Some additional comments on regulatory issues are included later in this chapter (Section 1.7). 

The rate and extent to which the active moiety is absorbed from a pharmaceutical dosage form and becomes available at the site(s) of action. Reliable measurements of drug concentrations at the site(s) of action are usually not possible. The substance in the general circulation, however, is considered to be in equilibrium with the substance at the site(s) of action. Bioavailability can be therefore defined as the rate and extent to which the active pharmaceutical ingredient or active moiety is absorbed from a pharmaceutical dosage form and becomes available in the general circulation. Based on pharmacokinetic and clinical considerations it is generally accepted that in the same subject an essentially similar plasma concentration time course will result in an essentially similar concentration time course at the site(s) of action. 

Fages, J., Rodier, E., Chamayou, A., and Baron, M. (2007). Comparative study of two processes to improve the bioavailability of an active pharmaceutical ingredient Kneading and supercritical technology. Kona-Powder Part, 25, 217-229. 

Drug formulating in nanosuspension form enhances the saturable concentration of active pharmaceutical ingredients, dissolution rate as well as bioavailability of the dmg. 

Some drug absorption enhancers are capable of loosening tight junctions (zonula occludens) and thereby facilitate paracellular absorption of drug molecules and improve the bioavailability of active pharmaceutical ingredients with low membrane permeability. The penetration enhancers include chelating agents [e.g., ethylenediaminetetraacetic acid), toxins [e.g., zonula occludens toxin), plant-derived materials [e.g., aloe vera gel), and cationic polymers. Polycationic lipophilic-core dendrons, which form lipophilic ion-pairs with heparin, were studied as a system for oral delivery of heparin. ... 

Polymorphism plays a crucial role in the preparation of active pharmaceutical ingredients (APIs), and the possibility to predict and control the crystallization of a specific polymorph is today of great interest for many applications in the pharmaceutical industry. Although identical in their chanical composition, different polymorphs often exhibit important differences in solnbility, dissolution rate, stability, melting point, density, and many other properties that significantly affect the efficacy, bioavailability, and safety of APIs (Llinas and Goodman 2008). 

There are a number of chemistry books available related to computational materials science and to modeling of molecular solid state, but none of the books cover current pharmaceutical industry applications. The intention of this book is to highlight the importance of the computational pharmaceutical solid-state chemistry and to fiU the gap in the current hterature. The book examines the state-of-the-art computational approaches to guide and analysis of solid form experiments and to optimize the physical and chemical properties of active pharmaceutical ingredient (API) related to its stability, bioavailability, and formulatability. While aU methods and approaches described in the book appear to be state of the art, the book is... 

Pharmaceutical excipients are formally considered as substances that are included in the manufacturing process of a pharmaceutical product and that are not the pharmacologically active drug or prodrug [1]. In pharmaceutical dosage form they possess a wide variety of functional roles such as modulation of solubility and bioavailability of Active Pharmaceutical Ingredients (APIs), improvement of stability of API in dosage forms, maintenance of its polymorphic form and conformation, maintenance of pH and/or osmolarity of liquid formulations, antioxidant activity, emulsifier, propellant of... 

Although therapeutic efficacy is the primary concern for an active pharmaceutical ingredient (API), the solid state form i.e., the crystalline or amorphous form) of an API can be critical to its pharmacological properties, such as bioavailability, and to its development as a viable drug candidate. Recently,... 

Demand for chiral compoxmds continues to increase, mainly for use in pharmaceuticals but also in other industries such as flavor, fragrance, cosmetics, and agricultural chemicals. Chiral active pharmaceutical ingredients (APIs) were previously usually formulated as racemates the preference now is for single enantiomers. The switch from a racemic compound to a single enantiomer of API is required to extend life-cycle management and also to improve the bioavailability and efficacy of drugs. 

In its Notice on "Studies of Prolonged-Action Forms in Man" dated 1987 09) the EC introduces the term of active principle presented in "pharmaceutical forms." This concept may apply to prodrugs, but only indirectly because the substance contained as such in the pharmaceutical form is not exactly the active principle. Similarly, in the council recommendation of 1987 on Investigation on Bioavailability (20), the terms active drug ingredient or therapeutic moiety of a drug are used to define the chemical species that should be measured. Finally, in a newer definition of bioavailability, the term active substance is used (21). 

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