Drug substances partition coefficient

Impurity profiling usually, salt formation enhances purity of drug substance Partition coefficient c log P Aqueous solubility as a function of pH... 

We are concerned with solubility in polar solvents such as water and in nonpolar solvents such as lipids. More specifically we are interested in a drug s partition coefficient, which is the relative solubility between these two phases. Such a coefficient is determined by dissolving the substance in an aqueous solution and equilibrating it by agitation with an organic solvent.1 The ratio of the concentration of the drug in the two phases is the partition coefficient. Any ratio greater than 0.01 indicates appreciable lipid solubility. 

The ending caine stems from cocaine, the first clinically employed local anaesthetic. Procaine and tetracaine are ester-linked substances, the others are amides. Amide bonded local anaesthetics usually contain two i s in their name, ester-bonded only one. In the structure drawings, the lipophilic portion of the molecule is depicted at the left, the amine at the right. The asterisk marks the chiral centre of the stereoisomeric drugs. Lipid solubility is given as the logarithm of the water octanol partition coefficient, log(P). 

The toxicological or cumulative effect of illicit drugs on the ecosystems has not been studied yet. Moreover, their fate and transport in the environment is to a big extent still unknown. Due to their physical-chemical properties (octanol-water partition coefficient, solubility, etc.) some of them, such as cannabinoids, are likely to bioaccumulate in organisms or concentrate in sediments whereas the rest, much more polar compounds, will tend to stay in aqueous environmental matrices. However, continuous exposure of aquatic organisms to low aquatic concentrations of these substances, some of them still biologically active (e.g., cocaine (CO), morphine (MOR) and MDMA) may cause undesirable effects on the biota. 

If it is assumed that the species is monomeric in both phases, the partition coefficient becomes the ratio of the solubilities, and it is simply sufficient to determine the solubility of the drug substance in the solvent (since it is assumed that the solubility is already known in water) ... 

What are the pA a value(s), partition coefficients, solubilities and stability of a drug substance under development ... 

C. Lead can substitute for calcium in the bone crystal lattice, resulting in bone brittleness. Bone may become a reservoir for other substances as well. Several drugs, such as chlorpromazine, may accumulate in the eye. Drugs with extremely high Upid-water partition coefficients tend to accumulate in fat, while basic amines tend to accumulate in the lungs. Many agents bind avidly to albumin in the blood. 

The partition coefficient Kq of an organic compound in the 1-octanol/water system is used to assess the bioaccumulation potential and the distribution pattern of drugs and pollutants. The partition coefficient of imidazole and ILs strongly depends on the hydrogen bond formed by these molecules and is less than one due to the high solubility in water. The low value of the 1-octanol/water partition coefficient is required for new substances, solvents, insecticides to avoid bioaccumulation. Kqw is an extremely important quantity because it is the basis of correlations to calculate bioaccumulation, toxicity, and sorption to soils and sediments. Computing the activity of a chemical in human, fish, or animal lipid, which is where pollutants that are hydrophobic will appear, is a difficult task. Thus, it is simpler to measure the 1-octanol/water partition coefficient. This parameter is used as the primary parameter characterizing hydrophobisity. 

The permeability, P (P = Pc x D), of a nonpolar substance through a cell membrane is dependent on two physicochemical factors (1) solubility in the membrane (Pc), which can be expressed as a partition coefficient of the drug between the aqueous phase and membrane phase, and (2) diffusivity or diffusion coefficient (D), which is a measure of mobility of the drug molecules within the lipid. The latter may vary only slightly among toxicants, but the former is more important. Lipid solubility is therefore one of the most important determinants of the pharmacokinetic characteristics of a chemical, and it is important to determine whether a toxicants is readily ionized or not influenced by pH of the environment. If the toxicant is readily ionized, then one needs to understand its chemicals behavior in various environmental matrices in order to adequately assess its transport mechanism across membranes. 

ASER relates a property of a series of drug substances in a given condition, such as solubility in water (Sw) and partition coefficient in water-octanol mixture (Kwo), to a sum of solute descriptors as given by ... 

By the time the clinical program has entered phase 3, the sponsor should provide a full description of the physical, chemical, and biological characteristics of the drug substance. For example, most of the following should be evaluated and submitted solubility and partition coefficient, pKa, hygroscopicity, crystal properties/morphology, thermal evaluation, X-ray diffraction, particle size, melting point, and specific rotation stereochemical consideration. Proof... 

The absorption was correlated to the octanol-water partition coefficients of the drugs, suggesting that prediction of absorption from partition data is possible [30, 31]. Polymers such as Nylon-6 (polycaprolactam) are known to adsorb drug substances such as benzocaine [32],... 

Water solubility (or aqueous solubility) is the maximum amount of a given substance that can dissolve in pure water at a particular temperature. Water solubility is a critical parameter, as drugs hitting the stomach must dissolve (be soluble) in gastric fluids to enable their absorption, transport, and delivery to target organs (e.g. the liver). The solubility of a substance in water is also helpful in determining the dispersion and fate of chemicals in the environment, and for this, water solubility is related to other chemical parameters (e.g. the octanol-water partition coefficient KOW). 

The classical measurement of LogP is the shake flask method [17]. A known amount of drug is dissolved in a flask containing both octanol phase and aqueous buffer at controlled pH to ensure the existence of only nonionic form (at least two units from the drug pA) ). The flask is shaken to equilibrate the sample between two phases. There must be no undissolved substance present in both phases. After the system reaches its equilibrium, which is time- and temperature-dependent, the concentration of drug is analyzed by HPLC in both phases. Partitioning coefficient is calculated as... 

Partition coefficient discussed above represents oil/water equilibrium distribution of only neutral forms of a substance. The distribution at different pH is described by LogD, which is the logarithm of the ratio of the concentrations of all forms of analyte in oil and water phases at particular pH. Logarithm of distribution coefficient at pH 7.4 is often used to estimate the lipophUicity of a drug at the pH of blood plasma. 

Studies of the extent of absorption in humans, or intestinal permeability methods, can be used to determine the permeability class membership of a drug. To be classified as highly permeable, a test drug should have an extent of absorption >90% in humans. Supportive information on permeability characteristics of the drug substance should also be derived from its physical-chemical properties (e.g., octanol water partition coefficient). 

The diffusion coefficient of the dmg in the skin will be determined by factors such as molecular size, shape and charge the partition coefficient will be determined not only by the properties of the drug but also by the vehicle as this represents the donor phase, the skin being the receptor phase. The quantity p can be approximated by experimentally determined oil/water partition coefficients. Thus, substances that have a very low oil solubility will display low rates of penetration. 

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