Solubility parameters from maxima in solubility/solvent plots

Solubility data of a substance in solvents with known solubility parameters have been used graphically in the past to determine the solubility parameter of the solute. A multiple regression method of handling this is presented. It gives rise to self-consistent solubility parameters, but the solvent molar volumes calculated are anomalous, pointing to the presence of factors not accounted for in the traditional approach to solubility parameter determination through solubility determination.     

Solution thermodynamics of some potentially long-acting norethinedrone derivatives III. Measurement of aqueous solubilities and the use of group free energy contributions in predicting partition coefficients

The solubilities in water of norethindrone and 7 of its derivatives have been measured and the results compared with the values predicted by a theory of additivity of group contributions to the free energy transfer of solutes between hydrocarbon and water. Since agreement between the two is reasonable, it was shown how the aqueous solubilities of very hydrophobic derivatives can be estimated where they are too low for measurement.     

Isocratic chromatographic retention data for estimating aqueous solubilities of acidic,basic and neutral drugs

For 108 compounds of diverse chemical character (including drug molecules) isocratic reversed-phase liquid chromatographic retention parameters have been used in modifications of the Hildebrand-Scott equation to estimate compound aqueous solubility. The relationships found are valid for both liquids and crystalline solids, as well as for stronger (pK_a > 6.5) bases that are chromatographed in a partially ionized state. It is observed that there is a significant constant difference in behaviour between acid and alcohol molecules and neutral and base molecules. This difference can be empirically corrected for during solubility estimations. Comparison of the use of octan-l-ol/water distribution coefficients in these equations shows that the use of isocratic chromatograhic retention parameters lead to significantly better estimations of compound aqueous solubility.     

Quantitative mechanistic studies in simultaneous fluid flow and intestinal absorption using steroids as model solutes

The interplay of flow-rate, aqueous boundary layer and membrane permeability coefficients, solute lipophilicity and intestinal length has been quantitatively determined for the in situ situation of bulk fluid flow and concurrent steady-state absorption of steroids in the small intestines of the rat. Seven steroids ranging in 3 orders of magnitude in n-octanol/water partition coefficients were used.The results followed the physical model predictions described by:

$\text{C(?)}\text{C(0)}\text{=exp}\text{?}\text{2πγ?}\text{Q}\text{·}\text{P}{}_{\mathrm{aq}}\text{1+P}{}_{\mathrm{aq}}\text{P}{}_{\mathrm{m}}$

where $\text{C}\text{?}\text{C}\text{(0)}$ is the fraction of steroid remaining in the intestinal lumen of length ?, r is the effective lumenal radius, Q is the flow-rate, P_aq and P_m are the respective aqueous boundary layer and membrane permeability coefficients. The log fraction of steroids remaining in the lumen was linear with intestinal length at various flow rates. The fraction absorbed increased with slower flow-rates at any given length due to the longer residence time. The fraction of steroid absorbed vs log partition coefficient profiles as a function of flow-rate were significantly sigmoidal. The absorption rates of progesterone were aqueous boundary layer-controlled and the less lipophilic hydrocortisone were membrane-controlled. It is significant that the permeability of the aqueous boundary layer is proportional to Q^0.44.     

Toxicity of bis(tri-n-butyltin)oxide in the rat. I. Short-term effects on general parameters and on the endocrine and lymphoid systems

Male and female Wistar rats were fed bis(tri-n-butyltin)oxide (TBTO) at 0, 5, 20, 80, or 320 mg/kg diet for 4 weeks. Clinical signs and decreases in feed and water consumption were observed in the 80 and 320 mg/kg groups. The serum transferase activities (alanine amino transferase and aspartate amino transferase were increased at 20 (males only), 80, and 320 mg/kg. The serum glucose and liver glycogen concentrations were lowered in the 320 mg/kg group. At 80 and 320 mg/kg the serum IgG level was reduced and IgM level was increased. Compared to controls the mean relative weight of the thymus was decreased at 20 (males), 80, and 320 mg/kg. In the groups receiving 80 or 320 mg/kg microcytic anemia was found. The white blood cell counts were decreased, due to the reduction in the number of lymphocytes in the 80 (males) and 320 mg/kg groups. The concentration of neutrophilic granulocytes was increased in the highest dose group. Histopathologic effects included a dose-related lymphocyte depletion of thymic cortex and of T lymphocytes in spleen and mesenteric lymph nodes. In the spleen also depletion of iron stores was found, and in the medullary sinuses of mesenteric lymph nodes, rosettes of erythrocytes were found around mononuclear cells; the occurrence of rosettes increased with dose from 5 to 80 mg/kg, and appeared to be the most sensitive parameter. A low incidence of areas of liver necrosis with inflammatory reaction and bile duct hyperplasia was found in the 320 mg/kg group. A viral or bacterial etiology could be demonstrated for these liver lesions, but they appeared associated with TBTO-induced ulcerative inflammation of the common bile duct as shown in an additional study. In 6-week studies exposure of male weanlings to the 0, 20, and 80 mg/kg diets, the serum insulin concentration in the treated groups was decreased, although the response to glucose challenge was unaffected. The serum thyroxin and thyrotropin (TSH) concentrations were reduced, whereas the luteinizing hormone (LH) concentration was increased in the 80 mg/kg group. The concentrations of follicle-stimulating hormone (FSH) and corticosterone were not changed. The release of LH and FSH was enhanced in the 80 mg/kg group and a tendency toward reduced release was found for TSH. Using immunocytochemistry a dose-related reduction was found in the number and staining intensity of TSH-producing cells in the pituitary, correlating with histopathologically decreased activity of the thyroid.(ABSTRACT TRUNCATED AT 400 WORDS)     

Ophthalmic solution buffer systems I. The effect of buffer concentration on the ocular absorption of pilocarpine

Miosis-time profiles were obtained using rabbits following the instillation of 25.0 μl of 1.0% pilocarpine nitrate solutions, which were buffered at a pH of 4.75 with different concentrations of citrate buffer. Relative pharmacological response, as measured by the areas under the miosis-time profiles and the maximum observed pupillary diameter changes, decreased as the citrate buffer concentration was increased. A reduction in the miosis-time profile area of greater than 5-fold was observed at the highest buffer concentration studied. The study demonstrates that a non-drug formulation component, such as a buffer system, can dramatically affect the relative pharmacological response from a simple ophthalmic solution dosage form. These results are of importance both in basic ophthalmic research studies and in ophthalmic product research and development.     

Ellipticine derivatives interacting with model membranes. Influence of quaternarization of nitrogen-2

Four compounds of the ellipticine family were examined in their interaction with liposomes and with an isolated bacterial membrane. The physicochemical methods used detected only minor differences between the properties of the amphiphilic drugs (ellipticine and 2-methyl-ellipticinium) and the two dipolar drugs (9-hydroxy-ellipticine and 2-methyl 9-hydroxy-ellipticinium). The amphiphilic drugs were able to become associated to anionic liposomes in a 20–30% excess of charge neutralization, and seem to penetrate deeper into the lipid layer than the two dipolar drugs. It was also shown that ellipticine penetrates deeper into liposomes membrane than into natural membrane used.In contrast with what can be postulated from the literature dealing with the behaviour of quaternarized drugs, it seems that ellipticine and its quaternarized analogues present fast diffusion through multilayered vesicles.On the whole, the membrane effects of the ellipticines studied here are not different for quaternarized drugs and for drugs not permanently charged, but are influenced by the existence on the molecules of a second polar function.     

Prediction of the solubility of griseofulvin in glycerides and other solvents of relatively low polarity from simple regular solution theory

Regular solution theory is applied to literature values of the solubility of griseofulvin in hydrocarbons and in other solvents of relatively low polarity. The solubility parameter of griseofulvin is calculated as $\text{10.2 ± 0.2}\text{cal}{}^{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}\text{·}\text{cm}{}^{\mathrm{<mtext>?</mtext><mtext>3</mtext><mtext>2</mtext>}}\text{at 25 °}\text{C}$. The relatively high solubilities of griseofulvin in polar, non-hydrogen-bonded solvents are interpreted in terms of dipolar or hydrogen-bonding interactions between solute and solvent, whereas the sub-ideal solubilities in alcohols and water are attributed to solvent self-association. The solubilities of griseofulvin in the glycerides are predicted from regular solution theory in its simplest form, assuming that London dispersion forces are the most important interactions in solution. The solubility parameter of each solvent is calculated from its refractive index. The predicted values agree well with the experimental values of solubility in the triglycerides and diglycerides, except when the hydrocarbon component is so high that the solvent is behaving effectively as a hydrocarbon. The solubilities of griseofulvin in the monoglycerides are about one-fifth of the predicted values, and this is attributed to appreciable solvent self-association by hydrogen-bonding.     

Theoretical model studies of intestinal drug absorption V. Non-steady-state fluid flow and absorption

A reasonably realistic physical model has been described for the simultaneous longitudinal spreading, fluid flow and absorption of drugs in solution under non-steady-state conditions m the small intestinal tract. Various input cases included first-order and zero-order stomach emptying and input from an infinite drug reservoir at constant infusion rate. The mathematical solutions were unique and rigorous. Theoretical simulations using reasonable physical parameter values illustrated the interrelationships of the longitudinal spreading diffusion coefficient, flow rate, apparent permeability coefficient and intestinal length on the change in concentration—distance profiles with time and the kinetics of appearance of unabsorbed drug at the end of the intestinal segment. The model is accessible to the design of intestinal absorption experiments and data interpretation on a quantitative mechanistic basis and also provides the way for studying intestinal absorption under more realistic situations.     

Pro-drugs as drug delivery systems XIII. Kinetics of decomposition of N-Mannich bases of salicylamide and assessment of their suitability as possible pro-drugs for amines

The kinetics of decomposition of various N-Mannich bases of salicylamide in aqueous solution at 37°C was studied to assess their suitability as pro-drugs for amino compounds. The decomposition, yielding salicylamide, amine and formaldehyde in stoichiometric amounts, showed bell-shaped pH-rate profiles which could be accounted for by assuming spontaneous decomposition of both neutral and protonated Mannich base and unreactivity of the derivatives in the anionic form. For the Mannich bases with the amines piperidine, α-alanine, methylamine and morpholine, the half-lives of decomposition at pH 7.40 and 37°C were 14, 17, 28 and 41 min, respectively, suggesting that salicylamide N-Mannich bases are possible candidates as pro-drugs for compounds containing a primary or secondary amino group. N-Amidomethylation of the amines with salicylamide resulted in a pronounced lowering of their basicity corresponding to 3–4 pK_a units which may be of potential utility for the application of N-Mannich bases as pro-drug forms for amines.     

An investigation of the effects of phenobarbitone on the pharmacokinetics of norethindrone in the rat using liver perfusion and everted gut sacs

Previous in vivo studies have suggested that phenobarbitone increases the first pass clearance of norethindrone in the rat by induction of enzymes both in the gut wall and liver. In the present study phenobarbitone caused an increase in both the production of highly polar ether-extractable metabolites and the conjugation of the steroid as it crossed the wall of the everted gut sac preparation. In addition, there was a marked increase in the uptake of norethindrone into the liver followed by increased phase I metabolism in the isolated perfused liver. As expected for a highly cleared drug, enzyme induction had no measurable effect on the terminal half-life of norethindrone in the perfused liver preparation.     

Solubilization and stabilization of an investigational antineoplastic drug (NSC no. 278214) in an intravenous formulation using an emulsion vehicle

The use of parenteral fat emulsions for development of an extemporaneous preparation of an intravenous formulation of a poorly water-soluble and unstable investigational anticancer agent (NSC no. 278214) is presented. The incorporation into a commercial fat emulsion of the drug, dissolved in dimethylacetamide-cremophor solution, results in a suitable parenteral formulation in which the drug is approximately 100-fold more stable than in simple aqueous solutions.     

A comparison of the physical properties of some sulphacetamide eye ointments commercially available in the U.K.

The rheology, particle size distribution and drug release, measured by dissolution and agar diffusion techniques, of 5 eye ointments containing sulphacetamide sodium has been studied. Although the particle size distributions of 2 B.P. products (6% strength) were similar (mean particle sizes of 13.5 and 14.7 μm) their consistency and drug release patterns were different. All ointments exhibited shear breakdown during continuous shear rheology. A linear relationship was found between the quantity of drug released by agar diffusion techniques and the amount dissolved after 60 min by dissolution. The B.P. ointments released their drug more slowly and, in most cases, to a lesser extent than the other 3, non-official ointments studied (strengths of 2.5, 6 and 10% w/w). The 2.5% strength ointment (w/o emulsion) was considered equivalent to the B.P. products.     

Free radical formation from anthracycline antitumour agents and model systems--I. Model naphthoquinones and anthraquinones

Several naphthoquinones and anthraquinones were chosen as simple models of the anthracycline drugs and their semiquinone radical anions were generated by various methods. With the exception of 1,4-naphthoquinone, all of the quinones studied gave radicals that were highly reactive with oxygen, but which, in its absence, were stable over a limited pH range. The radicals were studied using electron spin resonance (ESR) spectroscopy and an examination was made of the effect on the distribution of the unpaired electron, of introducing various groups into the conjugated ring system. Hydroxyl groups capable of participating in strong intramolecular hydrogen bonding with neighbouring carbonyl groups had a marked influence on electron distribution and reduced the effects of intermolecular hydrogen bonding of the radicals with solvent molecules.     

Effects of morphine and pentobarbital on mouse and rat renal transport systems.

The effects of morphine and pentobarbital administered by pellet implantation have been examined for possible nephrotoxic effects in the rat and the mouse. In particular, the effects of these drugs on various renal transport mechanisms were examined. Morphine was found to disrupt renal transport, tissue electrolytes, but not tissue oxygen consumption 24 hr after pellet implantation in the mouse. By 72 hr, however, all parameters examined had returned to control levels despite the continued presence of morphine. The specificity of this effect was demonstrable through the use of naloxone. This antagonist reversed completely all of the morphine effects in the mouse. In the rats, morphine altered only p-aminohippurate (PAH) transport. Pentobarbital reduced PAH and tetraethylammonium (TEA) transport in the rat. Kidney slices from mice implanted with pentobarbital showed significant increases in the uptake of PAH and α-aminoisobutyrate (AIB). No disruption of tissue electrolytes or water was observed in either species with pentobarbital administration.     

Enthalpy-entropy compensation analysis of pharmaceutical,biochemical and biological systems

Although linear free-energy relationships are familiar research tools in pharmaceutical and biochemical science, the analysis of data in terms of a further extrathermodynamic analysis, namely enthalpy-entropy compensation, is little used. This review attempts to draw attention to this latter procedure and describes the advantages and disadvantages of the method by using examples taken from the recent literature. Consideration is first given to the manner in which the analysis should be performed, and to the significance of found compensation relationships. Secondly, the analytical procedure is applied to data derived from a number of phenomena of pharmaceutical and biochemical interest, including, liquid-liquid distribution, Chromatographic retention, aqueous solubility, complexation, film spreading, liposome-water partitioning, biological membrane permeation and receptor/enzyme-small molecule interactions. Results indicate that enthalpy-entropy compensation analysis, when performed using the statistically correct coordinate plane of enthalpy versus free-energy, can be a most valuable tool for examining the effect of physicochemical structure on various phenomena, for verification of similarity in behaviour, and for indicating outliers from general relationships.     

Drug-protein conjugates--V. Sex-linked differences in the metabolism and irreversible binding of 17 alpha-ethinylestradiol in the rat

Sex-linked differences in the disposition, biotransformation, excretion and irreversible binding of [6, 7-3H]17 alpha-ethinylestradiol [( 3H]EE2) in Wistar rats have been observed. Three hours after i.v. administration of [3H]EE2 (5 micrograms/kg) the livers of males contained twice as much 3H-labelled material as those of females. The biliary metabolites were largely glucuronides in both sexes, but males also excreted arylsulphates. The principal metabolites liberated from biliary conjugates by enzymes were 2-hydroxyEE2 and 2-methoxyEE2 in females and males, respectively. Biliary elimination of 3H over 3 hr was slightly greater in males (P less than 0.05). Radiolabelled material was irreversibly bound to hepatic microsomal and soluble protein. The material bound to microsomes represented 0.24 +/- 0.07% (mean +/- S.D.) of the dose in males and 0.56 +/- 0.10% in females (P less than 0.001). Oxygenation of the steroid D-ring was not indicated, and 2-hydroxyEE2 appears to be the precursor of the reactive metabolite. The metabolic basis of the sex-linked difference in irreversible binding is discussed.     

Facilitated percutaneous absorption: A model system

The transport of a model anionic drug, methyl orange, across a liipid membrane has been studied. Various N-substituted di-isopropanolamines have been shown to facilitate the rate of transfer. Data are presented to show how the structure of the carrier molecules influences overall permeation.A mechanism is proposed by which anionic drug molecules may be effectively transported across the stratum corneum.