Genetic Variants of Na Transport Systems in Human Red Cells
Ronald L. Nagel in Genetically Abnormal Red Cells, 2019
The coupling of ion gradients permits that a co- or counter-ion can be transported uphill driven by a downhill movement of another ion partner. These ion pathways have recently been well defined in terms of their kinetic and equilibrium properties, as well as in their modes of operations. We call the attention to these types of transporters because in many studies of ion transport in red cells of patients with anemia and genetic variants of Hb, high values of K and Na fluxes have been interpreted as “increased leaks” or as “membrane defects”. Parker and Berkowitz1 stated in their recent review that “the functional defect in all these cases (hemolytic anemia) appears to be an increase in the passive permeability of the cells to Na and K.” Passive fluxes were defined as ouabain resistant (OR) or bumetanide and ouabain resistant; however, it is well known that permeability of lipid bilayers is several orders of magnitude lower and therefore it cannot be ascribed to movement of ions across this barrier. On the other hand, the relationship between cell age and the activity of ion transporters has not been yet defined in human red cells.
Solid Lipid Nanoparticles for Anti-Tumor Drug Delivery
Mansoor M. Amiji in Nanotechnology for Cancer Therapy, 2006
The anti-tumor drug salts typically have lipophilic molecular structures. The main obstacle against these salts from efficient loading into SLN is their ionic charges. For details of the drug loading mechanism of this class of compounds into SLN-based systems, refer to Section 36.4.1. In essence, it is about neutralizing the charge on the ionic drug salt with a counter ion. It may be argued that these extra steps can simply be avoided by using the free bases of these agents. However, the use of free base compounds will essentially lead to the same scenario described previously in Section 36.5.1.1. These poorly water-soluble free base compounds will likely be very slowly released, and the released drug concentrations will not be as high as compared to when the salt forms are used. The free base compounds may also require dissolution in organic solvents first during the preparation process to allow even mixing with the lipids. In general, it is preferable to use the water-soluble salt of an anti-tumor drug for SLN formulation whenever it is available.
High-Performance Liquid Chromatography
Joseph Chamberlain in The Analysis of Drugs in Biological Fluids, 2018
Another classical method for effecting extraction of charged compounds from aqueous phases is the technique of ion-pairing, which is also used in altering partition coefficients in HPLC. In the classical method, a counter-ion is added to the solution containing the ion to be extracted and association with a reduced charge is formed; this entity is then extractable with an organic solvent. Thus, for organic acids, a suitable counter-ion would be tetramethylammonium, while for organic bases, such ions as heptane sulfonate have been used. Much of the development of the use of paired ion chromatography is due to the work of Schill681 and Tomlinson et al.682 who have written several extensive reviews on the theory and practice of the technique.
Hydrophobic ion pairing-based self-emulsifying drug delivery systems: a new strategy for improving the therapeutic efficacy of water-soluble drugs
Published in Expert Opinion on Drug Delivery, 2023
Jinghan Xin, Mengdi Qin, Genyang Ye, Haonan Gong, Mo Li, Xiaofan Sui, Bingyang Liu, Qiang Fu, Zhonggui He
The lipophilicity of HIP complexes is mainly dependent on the type of counterions. The counterion structure, especially the length of counterion chains, should be firstly considered. Usually, the lipophilicity is proportional to the chain length of a counterion. The longer the chain, the greater the lipophilicity of the HIP complex [23,35]. Therefore, we can enhance the lipophilicity of the complexes by pairing with long-chain counterions. However, if the counterion structure is too bulky, it is not conducive to the membrane permeation and oral absorption. In this case, desired HIP complexes were usually achieved by customizing counterions [23,36,37]. In addition, the counterion concentration should also be considered. For most cases, hydrophilic biomacromolecules are constantly neutralized with an increase of the counterion concentration due to their increased lipophilicity after complexation [38]. However, when a surfactant is used as a counterion donor, micelles formed may dissolve the HIP complexes at a high concentration [39]. Moreover, drug molecular size [29], toughness, steric effect of the compounds [40], etc., may also affect the lipophilicity of HIP complexes.
A review of methods for solubility determination in biopharmaceutical drug characterization
Published in Drug Development and Industrial Pharmacy, 2019
Ardita Veseli, Simon Žakelj, Albin Kristl
Wang et al. [10] presented such a case showing that the quantity of the excess solid used affected the solubility of a dihydrochloride salt of a diprotic weak base. Essentially, the concentration of the counterion, chloride was altered in concomitance with the change in the amount of excess solid. In a pH region 2–5 where the monohydrochloride salt dictates the solubility, the drug which was firstly added as a dihydrochloride salt was converted to its monohydrochloride salt and chloride ions were released. As a result of this release, the solubility of the drug was supressed via the common ion effect. However, in this case, the physicochemical property of the drug needs to be emphasized. The compound possesses two pKas (3.1 and 7.7) and the disparity between the two pKas is what contributed to the alterations in solubility in the pH region 2–5 based on the added amount of solid. Therefore, the change in solubility should be attributed to the physico-chemical property of the drug rather than the intrinsic effect of excess solid on solubility [11].
A case study where pharmaceutical salts were used to address the issue of low in vivo exposure
Published in Drug Development and Industrial Pharmacy, 2019
Kalle Sigfridsson, Marie-Louise Ulvinge, Lena Svensson, Anna-Karin Granath
To increase dissolution rate in vivo, a common approach is to reduce particle size. Nanoparticle suspensions of different kinds are excellent for low doses and i.v. administration due to improved dissolution rate with smaller particles. However, with very sparingly soluble drugs or high doses (toxicological studies), the approach might not be sufficient. For the present API, data suggested that the dissolution process of the free base of the API will limit the fraction absorbed in humans. By using a suitable salt form of the compound, the dissolution rate increased and the risk of failure due to too low and/or variable bioavailability will thereby be reduced. The crystalline hemi-1.5-naphtalenedisulphonate salt of the API was a possible candidate for further development as were the chloride and hydrogen sulfate salts of the compound. The identity of the counter ion is probably of less importance. The investigated counter ions will create enough supersaturation for therapeutic levels and probably also for toxicological studies. The crucial points were then physical and chemical stability and in vivo tolerability. These properties were sufficient for the three salt forms, with a tendency to a small, if any, advantage for the hemi-1.5-naphtalenedisulphonate salt of the compound. From the present knowledge of the properties of the API, the compound fulfills the requirements for an immediate release (IR) dosage form, preferably based on a salt form of the API, as crystalline free base(s) may be associated with significant risk of insufficient and/or highly variable plasma levels.
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