Dissolution of weak acids under laminar flow and rotating disk hydrodynamic conditions: application of a comprehensive convection-diffusion-migration-reaction transport model

A steady-state mass transfer model that incorporates convection, diffusion, ionic migration, and ionization reaction processes was extended to describe the dissolution of weak acids under laminar flow and a rotating disk hydrodynamics. The model accurately predicted the experimental dissolution rates of benzoic acid, 2-naphthoic acid, and naproxen in unbuffered and monoprotic buffers within the physiological pH range for both hydrodynamic systems. Simulations at various flow rates indicated a cube root dependency of dissolution rate on the flow rate for a given bulk pH value for the laminar hydrodynamic system, as proposed earlier by Shah and Nelson (1975. J Pharm Sci 64(9):1518-1520) for neutral compounds. The model has limitations in its ability to accurately predict the dissolution of weak acids under certain conditions that imposed steep concentration gradients, such as high pH values, and for polyprotic buffer systems that caused the numerical solution to be unstable, suggesting that alternative numerical techniques may be required to obtain a stable numerical solution at all conditions. The model presents many advantages, most notably the ability to successfully predict the complex process under physiological conditions without simplifying assumptions, and therefore accurately representing the system in a comprehensive manner.     

The analysis of basic and acidic compounds using non-aqueous CE and non-aqueous CE-MS

It has been shown that non-aqueous capillary electrophoresis (NACE) can provide improved separations in comparison to those obtained using conventional CE under aqueous conditions (ACE). Previous work carried out in our laboratories involving initial investigations into the technique have been reported. Based on the findings of that work it was possible to separate a variety of basic pharmaceuticals from selected impurities and to obtain the successful separation of some hydrophobic sulphonic acids. The successful coupling of NACE to mass spectrometry (NACE-MS) has also been demonstrated.     

Dissolution of anecortave acetate in a cylindrical flow cell: re-evaluation of convective diffusion/drug dissolution for sparingly soluble drugs

Steady-state drug release rates were measured from a model cylindrical implant, comprised mainly of the sparingly soluble drug anecortave acetate, suspended as an obstacle in a cylindrical flow cell. Dissolution medium was delivered at a steady, slow flow rate (0.05-0.7 mLs/min) using an HPLC pump, and samples from the outflow were analyzed by direct injection onto an HPLC column. Release rates were determined as a function of flow rate for three different implant orientations--vertical, elevated to the center of the dissolution cell; horizontal, elevated; and horizontal, resting directly upon the flat porous inlet frit. Release rates were ranked as follows: horizontal, floor > horizontal, elevated>vertical, elevated. The steady, laminar flow enabled use of the finite element method (FEM) to simulate the dissolution process using convective diffusion/drug dissolution theory. Simulations predicted the absolute magnitude of the release rate to within < 10% for all situations, and predicted the power law exponent of the dependence of release rate on flow rate with great accuracy. The current method is more general than compendial methods that provide a dissolving surface that is uniformly accessible to the dissolution medium, or a shear rate that is uniform across the entire dissolving surface. The current approach may be utilized to provide estimates of dissolution rates for any geometry and set of hydrodynamic conditions that can be numerically calculated.     

Characterization of calcium fenoprofen 2. Dissolution from formulated tablets and compressed rotating discs

Calcium fenoprofen samples previously studied in powder form have been made into formulated tablets and into pure compressed discs. The wide variation in dissolution rate noted for powders is not noted in the early stages of tablet dissolution, all samples giving about the same rate in spite of variation in the disintegration rate. It is possible that smaller particles have been compressed or agglommerated to larger ones, or have been rendered hydrophobic by magnesium stearate. In later stages there is some intersample variation, apparently linked to larger particles in the parent active ingredient. Intrinsic dissolution rates from compressed discs cannot be influenced by any excipients as these are not present, or by particle size considerations as the area of the discs is constant. Rates differ only slightly after compression, and this is thought to be due to only partial retention of energetic differences following compression.     

Dissolution and partitioning behavior of hydrophobic ion-paired compounds

Purpose. This study was conducted to determine the effects of counterion hydrophobicity on organic/aqueous partition coefficients for hydrophobic ion paired (HIP) complexes. Furthermore, the coupled dissolution and reverse ion-exchange kinetics for dissolution of HIP complexes into aqueous electrolyte solutions were measured and mathematically modeled. Methods. HIP complexes of model drugs tacrine and l-phenylephrine were formed using linear sodium alkylsulfates and bis (2-ethylhexyl sodium sulfosuccinate). Equilibrium partition coefficients between chloroform and aqueous solutions for the complexes and the kinetics of dissolution of the complexes in buffered aqueous solutions were measured. Results. The chloroform/aqueous partition coefficients for l-phenylephrine/bis (2-ethylhexyl sodium sulfosuccinate) complexes decrease with increasing molar surface tension increment of salts added to the aqueous solution. The logarithm of the partition coefficient for a homologous series of alkyl sulfate complexes decreases as the hydrophilic-lipophilic balance number increases. Dissolution of HIP complexes in deionized water shows first order kinetics, whereas dissolution in aqueous electrolyte solutions shows biphasic kinetics. A kinetic model explains these dissolution rates. Conclusions. Solubility and dissolution rates for HIP complexes depend on the hydrophobic-lipophilic balance number of the organic counter ion as well as on the electrolyte composition of aqueous solutions. Reverse ion-exchange kinetics are sufficiently slow to allow HIP complexes to be considered simple prodrugs.     

Shark cartilage as source of antiangiogenic compounds: from basic to clinical research

The discovery that angiogenesis is a key condition for the growth of a tumor beyond a millimeter or two, brings about a new approach in the treatment of tumors using drugs able to inhibit the formation of new blood vessels. Also, it has been realized that antiangiogenic drugs can be useful in the treatment of other pathological processes, now classified as angiogenesis-dependent diseases. Initially, cartilage was considered as a possible natural source of antiangiogenic compounds due to its known avascular nature. To date, a number of in vitro and in vivo studies have suggested the existence of antiangiogenic and antitumor compounds in bovine and shark cartilage. However, the potential usefulness of shark cartilage in the treatment of cancer and other angiogenesis-dependent diseases have not been totally accepted due to (i) unsatisfactory patient outcome in clinical trials that have used shark cartilage in cancer patients, (ii) the lack of data that correlates bioavailability with pharmacological effects using oral shark cartilage. Thus, the objective of this review is to describe the main basic and clinical investigations reported in the literature, in which the antiangiogenic and/or antitumor properties of shark cartilage or of its extracts were evaluated. Possible explanations for conflicting results are discussed as well.     

Activity of pentosan polysulphate and derived compounds on vascular endothelial cell proliferation and migration induced by acidic and basic FGF in vitro

Pentosan polysulphate (PPS, SP 54, HEMOCLAR), a highly sulphated semi-synthetic polysaccharide of MW 4700 Daltons is as efficient as heparin in potentiating the mitogenic activity of acidic FGF (aFGF) on human umbilical vein endothelial cells (HUVEC). When added to basic FGF (bFGF), no effect was observed on these cells. However, PPS had a strong inhibitory effect on the growth of bovine aortic endothelial cells (BAEC), as did heparin. PPS was fractionated according to molecular weight and the activities of these fractions were compared. A PPS fraction of MW = 3200 Daltons represented the critical size required to affect cell proliferation induced by FGFs. We also report that acidic and basic FGFs are both chemotactic for BAEC and HUVEC. PPS and heparin, which were chemotactic alone on BAEC, potentiated acidic FGF-induced migration but inhibited the chemotactic response of basic FGF. These data suggest that PPS, although having a different structure, can mimic the in vitro activity of heparin on FGF-induced proliferation and migration of endothelial cells and thus the possibility of a specific heparin sequence being involved in the interactions with FGFs can be questioned.     

Development of a generic method to the solid-phase extraction of acidic compounds from complex matrices

A mixed-mode solid-phase extraction procedure was developed for the isolation and purification of acidic compounds from complex biological matrices. Urine samples were spiked with several acidic drugs and diluted in ammonium acetate buffer. Isolute HAX columns (a mixed-mode phase consisting of both hydrophobic and ion-exchange ligands) were conditioned with methanol and ammonium acetate prior to sample loading. Once the samples were loaded, the cartridges were rinsed sequentially with ammonium acetate and a 50:50 ratio of methanol and deionized water. The analytes were eluted with an 80:20 ratio of methanol and acetic acid. The eluates were evaporated to dryness and reconstituted to a final volume with a 98:2:0.1 ratio of deionized water, acetonitrile, and trifluoroacetic acid. Samples were analyzed by high-performance liquid chromatography. The absolute recoveries for most of the tested acidic drugs exceeded 80% at an original concentration of 1 microg/mL. Hydrophobic and ion-exchange sorbents were also investigated separately; however, the retention of the analytes suffered during sample application as well as the purity of the eluted extract. Results on anion-exchange columns show that the correct choice of counter-ion is extremely important to the retention of acidic analytes. The highest absolute recoveries were obtained when acetate was the counter-anion on the ion-exchange sorbent.     

Effect of age and sex on the plasma binding of acidic and basic drugs

Summary Protein binding of chlorpromazine, propranolol, meperidine, desipramine, salicylic acid and phenytoin was determined in plasma of 64 healthy volunteers (35 males and 29 females). An attempt was made to identify factors affecting the plasma protein binding of these drugs. Whereas plasma albumin levels decreased as a function of age in both sexes, α₁-acid glycoprotein levels increased with age, but the increase was more pronounced in males. The free plasma fraction of the acidic drugs (salicylic acid, phenytoin) and despiramine (a base) showed a significant (p<0.005) negative correlation with plasma albumin levels. The free fractions of the other three basic drugs (chlorpromazine, propranolol, meperidine) in plasma showed a significant (p<0.005) negative correlation with α₁-acid glycoprotein plasma levels. Plasma protein binding of salicylic acid, phenytoin and desipramine decreased as a function of age. Plasma protein binding of chlorpromazine, propranolol and meperidine was virtually unaffected by age or was slightly increased (chlorpromazine). Only in the case of salicylic acid could a statistically significant difference be demonstrated between males and females in the free fraction-age relationship. Stepwise multiple linear regression analysis, including age and blood chemistry values such as hematocrit, bilirubin, cholesterol, triglycerides, creatinine, BUN, albumin and α₁-acid glycoprotein as independent variables, identified age as the variable explaining most of the variability in plasma binding of salicylic acid, phenytoin and desipramine. For chlorpromazine, propranolol and meperidine α₁-acid glycoprotein was the most important determinant of plasma protein binding.     

Re-evaluation of anion-exchange HPLC for the analysis of acidic compounds

A number of weak and strong anion-exchange HPLC phases have been evaluated for the analysis of acidic drugs and related compounds. Using eluents with high organic content, reasonable chromatography could be obtained and widely differing compounds easily separated in isocratic mode. Retention was related to solute pKa and concentration of ammonium acetate in the eluent. All the phases showed an unexplained loss in retention with repeated use, although with one material; nucleosil SAX, this was low (15%) and considered acceptable. This material was also shown to be relatively stable under typical bioanalytical conditions.     

Dissolution,solubility and cooperativity of phenolic compounds from Hypericum perforatum L. in aqueous systems

The dissolution in water of phenolic constituents of St. John's wort (Hypericum perforatum L.) from a medicinal tea and a coated tablet formulation showed different dissolution profiles. In general, the flavonoid glycosides were well dissolved, followed by flavonoid aglycones and hypericin while hyperforin was only detectable at a very low level. Interestingly, hypericin exhibited much better extraction and dissolution rates than the similarly lipophilic hyperforin. When determining the octanol/water partition coefficient it became obvious that the solubility of pure hypericin in water increased upon addition of some phenolic constituents typical for Hypericum extracts. Most effective in solubilizing hypericin was hyperoside (hyperin, quercetin 3-O-beta-D-galactoside) which increased the concentration of hypericin in the water phase up to 400 fold in this model.     

Kinetics and mechanism of the basic hydrolysis of indomethacin and related compounds: a reevaluation

The kinetics of the hydrolysis of indomethacin and related compounds were studied in an alkaline medium at 25 degrees. The pseudo-first-order rate constants were evaluated from log absorbance versus time plots in the ultraviolet. These compounds showed a second-order rate constant at low concentrations of hydroxide ion and a first-order rate constant at higher concentrations of hydroxide ion.     

Convenient nonlinear model for predicting the tissue/blood partition coefficients of seven human tissues of neutral, acidic, and basic structurally diverse compounds

In this work, the tissue/blood partition coefficients of seven human tissues were calculated using a nonlinear regression analysis. The dataset contained 80 structurally diverse compounds distributing into the brain, kidney, muscle, lung, liver, heart, and fat, whose acidic and basic properties were also considered by introducing the three possible forms of the compound in the human body (neutral, cationic, and anionic forms). A total of 248 data points were there in the training set (eq 5: r = 0.877, s = 0.352; eq 6: r = 0.869, s = 0.362) and 49 data points in the testing set (eq 5: r = 0.844, s = 0.342; eq 6: r = 0.860, s = 0.311). It was also concluded that the same state (neutral, cation, and anion) of a compound has essentially identical partition coefficients between the same tissue composition and the blood in these tissues. Only the different content of the three tissue compositions (lipid, protein, and water) lead to the different partition coefficient in different tissues, which offered a significant conclusion for the drug's distribution research.     

Embryo-maternal distribution of basic compounds in the CD-1 mouse: doxylamine and nicotine

The intracellular pH of the early postimplantation rodent embryo (pHi) is alkaline with respect to the corresponding plasma of the pregnant dam. This transplacental pH gradient is of considerable importance in the accumulation of teratogenic weak acids by the embryo. The importance of pH in the partitioning of basic drugs across the early mammalian placenta has not been investigated. Theoretically, the maternal plasma should retain a higher concentration of basic drugs than the embryo due to a greater degree of drug ionization in the more acidic plasma. To explore the significance of pH partitioning upon the transplacental distribution of basic compounds, two bases, doxylamine and nicotine, were administered to pregnant CD-1 mice during early organogenesis. The maternal plasma and embryonic concentrations of the bases were measured and the resulting embryo/maternal plasma (E/P) ratio was calculated and compared to the ratio predicted by the Henderson-Hasselbalch equation. Following ip injection of nicotine on Day 9 of gestation, the E/P ratio was significantly greater than the predicted ratio 10 min after injection and continued to rise for 3 hr. For doxylamine succinate administered by oral gavage on Day 9 or 10, the E/P ratio was also significantly greater than the ratio predicted from the pH gradient. Our results indicate that the partitioning of these basic compounds between the maternal plasma and the early postimplantation rodent embryo is not a consequence of the pH gradient between the two compartments alone.     

Prediction of the disposition of nine weakly acidic and six weakly basic drugs in humans from pharmacokinetic parameters in rats

Various pharmacokinetic parameters--disposition half-life, t1/2,z, metabolic clearance CLm, volume of distribution V, intrinsic clearance of unbound drug CLuint, and unbound volume of distribution of tissues (distributive tissue volume/fraction of drug in tissue unbound, VT/fuT--are compared in rat and human for nine weakly acidic drugs, phenytoin, hexobarbital, pentobarbital, phenylbutazone, warfarin, tolbutamide, valproate, phenobarbital, and amobarbital, and six weakly basic drugs, quinidine, chlorpromazine, propranolol, pentazocin, antipyrine, and diazepam. With regard to all parameters, statistically significant correlations are obtained when parameters are plotted on a log-log plot. Correlation coefficients between the intrinsic parameters (CLuint or VT/fuT) were higher than those between the hybrid parameters (t1/2,z, CLm or V). In general, these drugs were metabolized ten times more rapidly in rat than in human. With regard to the tissue distribution of these drugs, there was little difference between rat and human. Predictions of CLm, V, and t1/2, in humans using rat data were successful for most drugs, with a few marked exceptions.     

Prediction of the disposition of nine weakly acidic and six weakly basic drugs in humans from pharmacokinetic parameters in rats

Various pharmacokinetic parameters—disposition half-life, t _1/2,z, metabolic clearance CL_m, volume of distribution V, intrinsic clearance of unbound drug CLu_t, and unbound volume of distribution of tissues (distributive tissue volume / fraction of drug in tissue unbound, V_T/fu_T—are compared in rat and human for nine weakly acidic drugs, phenytoin, hexobarbital, pentobarbital, phenylbutazone, warfarin, tolbutamide, valproate, phenobarbital, and amobarbital, and six weakly basic drugs, quinidine, chlorpromazine, propranolol, pentazocin, antipyrine, and diazepam. With regard to all parameters, statistically significant correlations are obtained when parameters are plotted on a log-log plot. Correlation coefficients between the intrinsic parameters (CLu_int or V_T/fu_T) were higher than those between the hybrid parameters (t_1/2,z, CL_m, or V). In general, these drugs were metabolized ten times more rapidly in rat than in human. With regard to the tissue distribution of these drugs, there was little difference between rat and human. Predictions of CL_m, V, and t_1/2, in humans using rat data were successful for most drugs, with a few marked exceptions.     

Preparation of solid drug/cyclodextrin complexes of acidic and basic drugs

One of the main obstacles in pharmaceutical applications of cyclodextrins is their increase of the formulation bulk. Even at maximum incorporation 500 mg of a solid drug/cyclodextrin complex will only contain between 50 and 125 mg of the drug, assuming a low molecular weight drug (MW 200 to 400 Dalton) and an average molecular weight cyclodextrin (MW about 1500 Dalton). In general, the complexation efficiency is low and consequently the complex powder contains a significant amount of empty cyclodextrin molecules. In the present study the complexation efficiency is increased by ionization of the drug molecule through addition of volatile acid (i.e. acetic acid) or base (i.e. ammonia) to the aqueous complexation media of basic or acidic drugs, respectively. The volatile acid or base was then removed during lyophilization and heating in a vacuum oven resulting in formation of solid cyclodextrin complexes of the unionized drug. Thus, the complexation efficiency was temporary increased by the ionization but then again decreased leading to formation of the thermodynamically unstable solid drug/cyclodextrin complexes. When dissolved the energy of the system was lowered by expelling the drug molecules from the cyclodextrin cavities resulting in formation of supersaturated drug solutions and ultimately precipitation of the drug.     

Micellar effects on the basic hydrolysis of indomethacin and related compounds

The kinetics of hydrolysis of indomethacin and related compounds was studied in an alkaline medium at 25 degrees C in the presence of anionic (sodium dodecyl sulfate) and cationic (hexadecyltrimethylammonium bromide) surfactants. The rate-surfactant profiles for rate inhibition in the presence of sodium dodecyl sulfate and rate enhancement in the presence of hexadecyltrimethylammonium bromide were analyzed in terms of the current theory of micellar effects.