Bioavailability and Granule Properties
Dilip M. Parikh in Handbook of Pharmaceutical Granulation Technology, 2021
Drug dissolution is a prerequisite for drug absorption, which, in turn, influences the rate and extent at which the administered dose of a drug reaches the general circulation. For many drugs that cross intestinal mucosa easily, the onset of drug levels will be controlled by the time required for the dosage form to release its drug content and then for the drug to dissolve. Dissolution is a process by which a solid substance dissolves. As a fundamental property of a solid, it is controlled by the affinity between the solid and the liquid medium that surrounds it. The proliferation of interest in drug dissolution may be attributed, primarily, to drugs that tend to be very hydrophobic, because the rate-limiting step in the drug absorption process from the gastrointestinal tract is often drug dissolution from the solid dosage form. Approximately 40% of the compounds that enter the development phase fail to reach the market [8]. The main reason for failure is poor biopharmaceutical properties, which include low aqueous solubility, chemical instability, insufficient intestinal absorption, intestinal and/or hepatic metabolism, biliary excretion, and high systemic clearance. Even a highly potent compound can become not developable unless it manifests adequate pharmaceutical properties. For example, to be effective, an orally administered compound must be absorbable across the gastrointestinal mucosa. Consequently, a major challenge confronted by the medicinal chemists is the design of a potential therapeutic agent that exhibits desired physicochemical properties, including intestinal permeability.
Toxicokinetics and Drug Disposition
Pritam S. Sahota, James A. Popp, Jerry F. Hardisty, Chirukandath Gopinath, Page R. Bouchard in Toxicologic Pathology, 2018
The rate and extent of absorption depend on the fundamental chemical properties of the molecule (i.e., pH-dependent ionization, polar surface area, polarity, lipophilicity), the drug substance properties, and the biological milieu. Drug absorption of highly permeable compounds is typically characterized as dissolution rate limited or solubility rate limited (Sugano et al. 2007), and while these two processes are linked, the distinction between dissolution and solubility is critical for understanding those drug characteristics that enhance or limit absorption. Dissolution is a time-dependent event and is the process of breaking apart the molecular forces holding together chemical solids and producing molecules that can be surrounded by solvent, that is, in solution. Solubility is a fundamental property of chemical structure and can be defined as the concentration of molecules that exist in a specified solvent (e.g., water, or gastric or intestinal fluid at a given pH) under specified conditions (e.g., at equilibrium with undissolved powder). These are important distinctions since large doses of relatively insoluble compounds are often administered in toxicology studies, where maximizing systemic exposure is critical, and the success of different approaches to increasing absorption and exposure depends on defining the rate-limiting step.
Gastrointestinal Tract as a Major Route of Pharmaceutical Administration
Shayne C. Gad in Toxicology of the Gastrointestinal Tract, 2018
Disintegration increases the surface area of the substance which enhances the probability of the solid dissolving into the solute. Surfactants, disintegrants, and lubricants are usually added to the drug during the manufacturing process to increase the solubility and dispersibility of the active ingredient. In the case of enteric-coated tablets, hydrophobic lubricants and extreme pressure may be applied during the manufacturing process to slow physically the dissolution process. Dissolution is the rate of availability of the active ingredient for absorption or the time required for a given amount of drug to be released into solution from a solid dosage form. Dissolution time is usually measured in vitro, under conditions that simulate those that occur in vivo, in experiments where the amount of drug in solution is determined as a function of time (Savjani et al., 2012; Rang et al., 2016). These processes permit the active ingredient to be released over a longer period of time and are critical to time-release drugs.
Development of sustained release gastro-retentive tablet formulation of nicardipine hydrochloride using quality by design (QbD) approach
Published in Drug Development and Industrial Pharmacy, 2018
Vijay S. Chudiwal, Sadhana Shahi, Swapnil Chudiwal
Dissolution is defined as a process in which the disintegrated solid solute enters into the solution. The dissolution test determines the time required for a specific percentage of the active ingredient in a dosage form to dissolve under the specified conditions. The dissolution test was carried out for batches using USP dissolution test apparatus (Type II Paddle type) (Lab India). The release studies were carried out at 50 rpm in 900 ml 0.1 N HCl (pH 1.2) at 37 ± 0.5 °C [28]. In total, 5 ml of aliquots were withdrawn at predefined intervals, and the volume of the dissolution medium was maintained by adding the same volume of fresh dissolution medium. The absorbance of the withdrawn samples was measured spectrophotometrically at λmax 240 nm. The experimental results obtained were expressed as mean ± SD.
Formulation strategy of nitrofurantoin: co-crystal or solid dispersion?
Published in Pharmaceutical Development and Technology, 2020
Xin-Yi Teoh, Fatin Nasuha bt Mahyuddin, Waqas Ahmad, Siok-Yee Chan
Unexpectedly, a simple PM of NF and HPMC shows a similar initial dissolution rate compared the co-crystal and overtook it in the later phase concluded that it can be a preferred method for industrial practice as far as return of investment is concerned. Dissolution is a dynamic process like our biological system. Purely depending on BCS classification that classifies the drug based on equilibrium values of solubility and permeability on formulation may not be sufficient to simulate the dynamic condition of our body. Therefore, ramification research from the current work would be the categorization of a poorly soluble drug in BCS class II into ‘physical mixture favored formulation’. As it may be merely the polymer wettability that could dramatically enhance the dissolution performances (but not solubility) of certain BCS class II candidates.
Simulated biological fluids – a systematic review of their biological relevance and use in relation to inhalation toxicology of particles and fibres
Published in Critical Reviews in Toxicology, 2021
Emma Innes, Humphrey H. P. Yiu, Polly McLean, William Brown, Matthew Boyles
The current body of literature has identified that particle and fibre dissolution is not always driven by pH, and likewise it is not only driven by fluid composition. When elucidated, there have been specific materials and specific formulations which correspond with specific dissolution mechanisms. For example, the presence of phosphate in the fluid has prevented the dissolution of specific materials due to the formation of insoluble salts such as cobalt phosphate (Stefaniak et al. 2009) and lead phosphate (Wragg and Klinck 2007). The influence of oxygen was particularly important in UO3 breakdown and similarly, the presence of peroxidase enzymes for CNT degradation. Fe(II) has been demonstrated to be especially involved in the generation of the highly reactive hydroxyl radicals, and therefore the antioxidant potential of the SLF will be important for Fe-containing materials (Vidrio 2009). Due to these material specific results, it would be pragmatic for further SLF developments to focus on how well the fluid matches the biological environment. With better biological mimicry, results are more likely to reflect in vivo behaviour regardless of the material under investigation. However, such efforts would result in a fluid of far greater complexity; and as eluded to above, this may affect the practicalities of performing the test in the current testing systems. Therefore, a rational approach is needed to ensure a balance between bio-relevance and usability.
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