The influence of excipients on the diffusion of ibuprofen and paracetamol in gastric mucus

The aim of this study was to examine the diffusion of commonly administered analgesics, ibuprofen and paracetamol, through gastric mucus. As ibuprofen and paracetamol are often formulated with alkalising excipients, or are commonly co-administered with antacids that have been demonstrated to alter their absorption, diffusion was also studied in the presence of a range of soluble and insoluble antacids or buffering agents. The effect of pH, which has been demonstrated to modify the properties of mucus, was also studied. Mucus was a significant barrier to diffusion for both drugs, compared to an unstirred aqueous layer with diffusion rates significantly lower in the presence of a mucus barrier for both drugs; ibuprofen diffusion also demonstrated a significant increase in the lag time. Paracetamol diffusion was not significantly affected by addition of any antacid, whereas ibuprofen rates were affected and the diffusion lag time for ibuprofen was significantly reduced in all cases. Isolated increases in pH increased the rate and reduced the lag time for ibuprofen diffusion. It was shown that mucus acts as a passive barrier in the case of paracetamol diffusion, and an interactive barrier to ibuprofen diffusion. Changes in mucus viscosity at different pH values may be responsible for the observed changes in ibuprofen diffusion rate.     

GI absorption of beta-lactam antibiotics II: deviation from pH--partition hypothesis in penicillin absorption through in situ and in vitro lipoidal barriers.

The absorption of propicillin from the rat stomach and small intestine in situ was examined as a function of recirculating solution pH. The in vitro interphase transport from an aqueous buffer of various pH values to the octanol phase was also studied for several penicillins by the use of a two-phase rolling cell. The rate--pH profiles obtained from both in situ and in vitro experiments deviated significantly from the dissociation curves. The degrees of the shifts were approximately 2 pH units for the in situ intestinal absorption of propicillin and in vitro transport of propicillin and cloxacillin, approximately 1.5 pH units for the in vitro transport of penicillin V, and 0.8 pH unit for the in situ stomach absorption of propicillin. These discrepancies from the classical pH--partition hypothesis can be interpreted by the permeation through the lipoidal barrier of the undissociated species of penicillins transported through the aqueous diffusion layer adjacent to the lipoidal surface. All in situ and in vitro experiments tend to support this theory.     

Effect of diffusion layer pH and solubility on the dissolution rate of pharmaceutical acids and their sodium salts. II: Salicylic acid, theophylline, and benzoic acid

The pH-solubility profiles of salicylic acid and theophylline, as determined by the addition of HCl or NaOH to their aqueous suspensions, were identical with those of their sodium salts except during phase transitions from acid to salt or vice versa. Supersaturated solutions were formed during phase transitions. Unlike the solubility profiles, the pH-intrinsic dissolution rate profiles of an acid and its salt differed greatly. Good conformity with the Noyes-Whitney equation was demonstrated when the solubility values under pH conditions as the diffusion layer thickness, h, approaches zero (Cs,h = 0) were used rather than solubilities under pH conditions of the bulk media (Cs). The pH when h approaches zero (pHh = 0) was estimated by equilibration of a dissolution medium with an excess of material. Good correlation was shown between the pHh = 0 values of benzoic acid estimated according to this method and the pHh = 0 values reported in the literature. The intrinsic dissolution rate constant, the ratio of the diffusion coefficient to the diffusion layer thickness (D/h), may be assumed constant when comparing the dissolution rates of salicylic acid, theophylline and sodium theophylline. On the other hand, D/h decreased significantly during dissolution of sodium salicylate due to a large increase in Cs,h = 0 and the consequent increase in viscosity in the diffusion layer. A simple method of predicting the dissolution rate of an acid or a salt at different pH values has been developed.     

Quantitaton of rate of gastrointestinal and buccal absorption of acidic and basic drugs based on extraction theory

Equations have been derived which quantitatively describe the rate of gastrointestinal and buccal absorption of acidic and basic drugs as a function of pH of aqueous lumenal contents and time. The equations have been used to fit observed data in the literature, and the estimated parameters are reported. An equation which describes the renal clearance of an acidic or basic drug as a function of urinary pH is also derived. In essence, the equations quantitate the pH-partition hypothesis and explain most, if not all, related observed data in the literature. The results suggest that the aqueous diffusion layer may not rate-limit absorption of monomeric drug molecules but that absorption is rate-limited by transfer of drug out of the membrane in vivo.     

Effect of diffusion layer pH and solubility on the dissolution rate of pharmaceutical bases and their hydrochloride salts. I: Phenazopyridine

The pH-solubility profile of phenazopyridine as determined by the addition of HCl or NaOH solutions to its aqueous suspension was identical to that of its hydrochloride salt except during phase transition from base to salt. With the addition of HCl to a suspension of the base, the pH dropped to a certain point and then remained constant until a supersaturated solution was formed. Only after a high supersaturation did precipitation of the hydrochloride salt occur. The solubility of the salt decreased at low pH due to a common ion effect. Unlike solubility profiles, the pH-intrinsic dissolution rate profiles of the base and its salt differed greatly. At low pH, the dissolution rate of the hydrochloride salt decreased with an increase in HCl concentration, whereas the dissolution rate of the base increased. The self-buffering action of the base and the increase in solubility, leading to a supersaturation of the diffusion layer was responsible for the increase in its dissolution rate with a lowering of the pH of the medium. Good conformity with the Noyes-Whitney equation was demonstrated when the solubility values under pH conditions such that the diffusion layer thickness approaches zero (Cs,h = 0) were used rather than solubilities under pH conditions of the bulk media (Cs). Supersaturation of the dissolution medium was observed during dissolution of the hydrochloride salt at pH 7.     

Determination of Solute Diffusion Properties in Artificial Sebum

Despite a number of studies showed that hair follicular pathway contributed significantly to transdermal delivery, there have been limited studies on the diffusion properties of chemicals in sebum. Here, the diffusion property of 17 chemical compounds across artificial sebum has been measured using diffusion cell. The diffusion flux showed 2 types of distinctive behaviors: that reached steady state and that did not. Mathematical models have been developed to fit the experimental data and derive the sebum diffusion and partition coefficients. The models considered the uneven thickness of the sebum film and the additional resistance of the unstirred aqueous boundary layer and the supporting filter. The derived sebum-water partition coefficients agreed well with the experimental data measured previously using equilibrium depletion method. The obtained diffusion coefficients in artificial sebum only depended on the molecular size. Change in pH for ionic chemicals did not affect the diffusion coefficients but influenced their diffusion flux because of the change of sebum-water partition coefficients. Generally, the measured diffusion coefficients of chemicals in artificial sebum are about one order of magnitude higher than those in the stratum corneum lipids, suggesting the hair follicle might have a non-negligible contribution to the overall permeation.     

The optimization of the availability of homologous quaternary ammonium compounds. 2. In vitro studies on the partition of homologous benzilic acid esters of dimethyl-(2-hydroxyethyl)-alkylammonium bromides]

The partition of homologous quaternary esters of benzilic acid is studied in a modified three-phase model according to Schulmann (water-n-octanol-water). The logarithms of the partition coefficients of the compounds increase linearly with increasing alkyl chain. The rate determining step for the interphase transport of hydrophilic compound is the diffusion through the organic diffusion layer. The rate constants for the transfer from the aqueous to the organic phase increase linearly with the corresponding partition coefficient, whereas the rate constants for the reverse reaction are not influenced. With increasing chain length the diffusion through the aqueous diffusion layer becomes rate determining for the interphase transport. Thus the rate constants for the transfer from the aqueous to the organic phase are independent of partition coefficients. The rate constants for the reverse transfer are inversely proportional to the corresponding partition coefficients. The half-lives of the transfer of the homologous compounds under sink conditions show a minimum between the heptyl and octyl derivative. The equilibration time decreases with increasing agitation, concentration and temperature. The significance of the results for biological problems is discussed.     

Systems approach to vaginal delivery of drugs V: in situ vaginal absorption of 1-alkanoic acids.

The vaginal absorption of a homologous series of ionizable compounds, the 1-alkanoic acids, was studied using a perfusion method with a rib-cage cell surgically implanted in the rabbit vagina. The absorption rates of these compounds followed first-order kinetics. The physical model previously used for the 1-alkanols, but accounting for the pKa and pH effects in the present case was employed in the analysis of the carboxylic acid data. The aqueous diffusion layer thickness was 0.031 cm. The permeability coefficient for the lipoidal pathway increased 3.5-fold per methylene group. Both values agree reasonably well with those obtained in the alcohol study.     

Systems approach to vaginal delivery of drugs III: Simulation studies interfacing steroid release from silicone matrix and vaginal absorption in rabbits.

A composite physical model involving the simultaneous receding boundary release of drug from a drug suspension-silicone polymer matrix system, diffusion across the aqueous layer, and passive transport across the vaginal membrane consisting of parallel lipoidal and aqueous pore pathways is described. Simulation studies with progesterone and hydrocortisone illustrate matrix release-limiting, membrane absorption, and aqueous diffusion layer-limiting cases when the cylindrical silicone delivery device is interfaced with the vaginal membrane of the rabbit.     

Effect of ‘unstirred’ water layer in the intestine on the rate and extent of absorption after oral administration

The presence of an aqueous diffusion layer or ‘unstirred’ water layer adjacent to the intestinal membrane has long been regarded as a potential barrier for intestinal absorption of compounds. Theoretical analyzes were performed in the present study to quantitatively determine the effect of this layer on the rate and extent of absorption of passively absorbed compounds with different membrane absorption half-lives (10 to 300 min) in humans, dogs, rabbits, rats and mice. Diffusion half-lives across this (40 μm thick) layer were estimated to be 5.8, 2.5, 1.1, 0.65 and 0.32 min, respectively, in the distended intestine of the above five species. These half-lives are reduced by about 5-fold when the intestine is about 80% ‘flat’ in fasting state. The results of extensive analysis indicate that the presence of such a layer is generally expected to have a relatively mild or insignificant effect on the rate of absorption and an insignificant effect on the extent of absorption. The study also indicates that an aqueous layer of 708 μm has practically no effect on the extent of absorption of progesterone, a highly lipophilic compound, in rats. For prediction of or correlation with the fraction of oral dose absorbed after oral administration, the present study indicates that use of apparent or effective permeability rather than unbiased or true wall (membrane) permeability, as advocated earlier by others, should generally suffice.     

Flux Across of Microneedle-treated Skin is Increased by Increasing Charge of Naltrexone and Naltrexol <Emphasis Type="BoldItalic">In Vitro</Emphasis>

PURPOSE: The purpose of this investigation was to evaluate the in vitro microneedle (MN) enhanced percutaneous absorption of naltrexone hydrochloride salt (NTX x HCl) compared to naltrexone base (NTX) in hairless guinea pig skin (GP) and human abdominal skin. In a second set of experiments, permeability of the major active metabolite 6-beta-naltrexol base (NTXOL) in the primarily unionized (unprotonated) form at pH 8.5 was compared to the ionized form (pH 4.5). METHODS: In vitro fluxes of NTX, NTX.HCl and ionized and unionized NTXOL were measured through microneedle treated or intact full thickness human and GP skin using a flow through diffusion apparatus. Solubility and diffusion samples were analyzed by HPLC. RESULTS: Both GP and human skin show significant increases in flux when treated with 100 MN insertions as compared to intact full thickness skin when treated with NTX.HCl or ionized NTXOL (pH 4.5; p < 0.05). MN increased GP skin permeability for the hydrophilic HCL salt of NTX by tenfold and decreased lag time by tenfold too. Similar results were found using human skin, such that skin permeability to NTX.HCl was elevated to 7.0 x 10(-5) cm/h. Permeability of the primarily unionized (unprotonated) form of NTXOL at pH 8.5 was increased by MN only threefold and lag time was only modestly reduced. However, MN treatment with the primarily ionized (protonated) form of NTXOL at pH 4.5 increased skin permeability fivefold and decreased lag time fourfold. CONCLUSION: Enhancement was observed in vitro in both GP and human skin treated with MN compared to intact skin with the salt form of NTX and the ionized form of NTXOL. We conclude that transdermal flux can be optimized by using MN in combination with charged (protonated) drugs that have increased solubility in an aqueous patch reservoir and increased permeability through aqueous pathways created by MN in the skin.     

Dissolution of acidic and basic compounds from the rotating disk: influence of convective diffusion and reaction

A mass transfer model was developed to describe the dissolution and reaction of acidic and basic compounds from a rotating disk in unbuffered water. Dissolution of two carboxylic acids, 2-naphthoic acid (1) and naproxen [(+)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid, 2], and the free base, papaverine (6,7-dimethoxy-1-veratrylisoquinoline, 3), in aqueous solutions (mu = 0.1 with KCI) at 25 degrees C were investigated. An automated dissolution apparatus, which consisted of microcomputer-controlled autoburets, was constructed to monitor and adjust the pH of the aqueous solutions during the experiments. Unique features of the mass transfer model include treatment of mass transfer as a convective diffusion process rather than a stagnant film diffusion only process; treatment of ionization and acid-base reactions as heterogeneous reactions; use of experimental diffusion coefficients for all species, particularly H+ and OH-; and application of boundary conditions that specify flux for surface ionization produced species. The model accurately predicted the dissolution rate assuming the solubility, pKa, and diffusion coefficient of the compound were independently known. The model also predicted pH at the solid-liquid surface, the flux of H+ from the surface, and the contribution of A- to the total acid flux as a function of bulk pH of the aqueous solution.     

Shapes of membrane permeability–lipophilicity curves: Extension of theoretical models with an aqueous pore pathway

The objective of this study was to rationalize the shape of membrane permeability–lipophilicity curves, when considering, in addition to the usual transcellular route, a parallel diffusion pathway through aqueous pores as present in biological membranes. The theoretical influence of different pH in donor and acceptor compartment and the molecular weight on the permeability curves was studied. We combined and extended two previously proposed absorption models, namely one describing diffusion through a simple membrane (two stagnant aqueous and two organic layers in series, no pores) as the sum of the two distribution steps at both membrane interfaces, and a second theoretical model considering the sum of different diffusional resistances through stagnant layers and membrane, respectively. Under certain conditions the equivalence of the two-step distribution model and the diffusional resistance model can be demonstrated. Incorporation of an aqueous diffusion pathway leads to an extended two-step distribution model. This theoretical membrane permeation model will permit a more physicochemical-based interpretation of permeation data and shows that combined log D values and molecular weight are important determinants for membrane transport processes through, e.g. Caco-2 monolayers and the mucosal GI membranes. We have demonstrated that the well-known sigmoidal permeability–lipophilicity relationship should be considered as a molecular weight-dependent set of sigmoidal relationships.     

Investigation of Solubility and Dissolution of a Free Base and Two Different Salt Forms as a Function of pH

No HeadingPurpose. To evaluate the effect of pH on solubility and dissolution rates of a model weak base, haloperidol, and two different salt forms, hydrochloride and mesylate.Methods. pH-solubility profiles were determined by using haloperidol base, haloperidol hydrochloride, and haloperidol mesylate as starting materials; concentrated or diluted HCl or NaOH solutions were added to aqueous suspensions of solids to adjust pH to desired values. Intrinsic dissolution rates were determined using intrinsic dissolution apparatus under various pH-stat conditions. Further, approximation of diffusion layer pH was estimated from that of 10% w/w slurries of drug substances in dissolution media, which were used to correlate with intrinsic dissolution rates of haloperidol and its salt forms under different pHs.Results. pH-solubility profiles of haloperidol base and its HCl salt were similar, while when the mesylate salt was used as starting material, it exhibited a higher solubility between pH 2 and 5. The higher solubility of the mesylate salt at pH 2–5 is attributed to its higher solubility product (K_sp) than that of the hydrochloride salt. The pH-solubility profiles indicated a pH_max (pH of maximum solubility) of 5, indicating that the free base would exist as the solid phase above this pH and a salt would be formed below this pH. Below pH 1.5, all solubilities were comparable due to a conversion of haloperidol base or the mesylate salt to the HCl salt form when HCl was used as the acidifying agent. These were confirmed by monitoring the solid phase by differential scanning calorimeter. When their dissolution rates are tested, dissolution rates of the mesylate salt were much higher than those of the free base or the HCl salt, except at very low pH (<2). Dissolution rates of free base and HCl salt also differed from each other, where that of HCl salt exhibits higher dissolution rates at higher pHs. A direct correlation of dissolution rate with solubility at diffusion layer pH at the surface of dissolving solid was established for haloperidol, its hydrochloride, and mesylate salts.Conclusions. Using pH-solubility and pH-dissolution rate interrelationships, it has been established that diffusion layer pH could be used to explain the observed rank order in dissolution rates for different salt forms. A non-hydrochloride salt, such as a mesylate salt, may provide advantages over a hydrochloride salt due to its high solubility and lack of common ion effect unless at very low pH.     

The effect of protein on the dissolution of phenytoin

Ultrafiltration of a continuous flow system was used to follow the dissolution of phenytoin powder in buffered solutions of pH 1, 4 and 7.4. The presence of either human serum albumin (HSA) or casein caused changes in both the absolute solubility and the dissolution rate. Normal protein binding cannot be responsible for the effects noted. It would seem likely that within the diffusion layer a higher degree of protein binding occurs than is possible in the bulk aqueous solution. The drug solubilized in this way is then released in solution in a form that is at least metastable with respect to phenytoin in normal solution. The effect of protein on phenytoin dissolution may well affect the bioavailability of the drug.     

Diffusion of lonizable Solutes Across Planar Lipid Bilayer Membranes: Boundary-Layer pH Gradients and the Effect of Buffers

The diffusion of weak acids or bases across planar lipid bilayer membranes results in aqueous boundary layer pH gradients. If not properly taken into account, such pH gradients will lead to errors in estimated membrane permeability coefficients, P _m. The role of the permeant concentration, the buffer capacity, and the physicochemical properties of both permeant and buffer on the magnitude and impact of such pH gradients have been explored. A theoretical model has been developed to describe the diffusion of both permeant and buffer species. Significant pH gradients develop depending on solution pH and the pK _a's, concentrations, and P _m values of both permeant and buffer. The relative error in experimentally determined P _m values was calculated as the ratio, r, between apparent P _m values (obtained from flux measurements using an equation which neglected boundary layer pH gradients) and its true value. Simulated r values ranged from 1 (0% error) to <0.01 (>100% error) for weak acids, decreasing with decreasing buffer capacity and increasing solute flux. The buffer capacity required for an r > 0.95 was calculated versus pH for permeants varying in pK _a and P _m. Membrane-permeable buffers significantly reduce boundary layer pH gradients through a feedback effect due to buffer cotransport. Apparent P _m values of p-hydroxymethyl benzoic acid across lecithin bilayer membranes at 25°C were obtained as a function of permeant concentration in various buffers [glycolic, 2-(N-morpholino)ethane-sulfonic, and formic acids]. Predictions agreed closely with experimental fluxes.     

The diffusion of sennoside A through a cellulose membrane

The diffusion rate of sennoside A through a cellulose membrane into water increased irrespective of the temperature conditions under which diffusion took place, when the membrane was irradiated with ultrasound. The results are consistent with the hypothesis of boundary layer disruption at the phase interface and their significance in the effect of ultrasonic energy on the aqueous extraction of senna pericarps is discussed.     

Evaluation of the Physicochemical Properties and Dissolution Characteristics of Mesalamine: Relevance to Controlled Intestinal Drug Delivery

The physicochemical properties of mesalamine and the effect of pH and buffer concentration on the dissolution rate of pure mesalamine and mesalamine with Carbopol 974P were investigated. The aqueous solubilities at 25 and 37°C were 0.844 and 1.41 mg/mL, respectively. Consistent with the observed pK _a1 (2.30) and pK _a2 (5.69) of mesalamine, the solubility–pH profile is increased at pH <2.0 and pH >5.5 and is minimized from pH 2.0 to pH 5.5. The flux data were consistent with the solubility data from pH 1.0 to pH 5.5. The flux increased and plateaued at pH values 5.5 to 7.0 and was dependent on the bulk buffer concentration. At low bulk buffer concentrations, mesalamine reduces the pH in the diffusion layer, which results in a decrease in flux. The medium with the highest buffer capacity has a greater ability to increase the surface pH and dissolution rate. The addition of Carbopol reduces the flux and the sensitivity of the dissolution rate of mesalamine to increasing bulk buffer concentration. This reduction is postulated to be due to neutralization of the basic dissolution media, gel formation, and possible drug–polymer interactions.     

Fish skin as a model membrane: structure and characteristics

Objectives Synthetic and cell‐based membranes are frequently used during drug formulation development for the assessment of drug availability. However, most of the currently used membranes do not mimic mucosal membranes well, especially the aqueous mucous layer of the membranes. In this study we evaluated catfish (Anarichas lupus L) skin as a model membrane. Method Permeation of hydrocortisone, lidocaine hydrochloride, benzocaine, diethyl‐stilbestrol, naproxen, picric acid and sodium nitrate through skin from a freshly caught catfish was determined in Franz diffusion cells. Key findings Both lipophilic and hydrophilic molecules permeate through catfish skin via hydrated channels or aqueous pores. No correlation was observed between the octanol/water partition coefficient of the permeating molecules and their permeability coefficient through the skin. Permeation through catfish skin was found to be diffusion controlled. Conclusions The results suggest that permeation through the fish skin proceeds via a diffusion‐controlled process, a process that is similar to drug permeation through the aqueous mucous layer of a mucosal membrane. In addition, the fish skin, with its collagen matrix structure, appears to possess similar properties to the eye sclera.     

Encapsulation and controlled release of hydrophilic pesticide in shell cross-linked nanocapsules containing aqueous core

In this study, amphiphilic biocopolymers, synthesized by mixing azidobenzaldehyde (Az) and an aqueous solution of carboxymethyl chitosan (CMCS), which self-assemble into nanocapsules with a aqueous core (ACN) in aqueous media followed by photo-cross-linking to obtain shell cross-linked nanocapsules, were used to develop a controlled release pesticide system. The system was characterized by TEM and DLS. Its encapsulation efficiency was determined. The obtained result showed that it is efficient to encapsulate methomyl reaching encapsulation efficiency as high as 90% in an aqueous medium at pH 4.0, which is mainly attributed to the hydrogen bonding adsorption between methomyl molecules and the inner surface of nanocapsules. Release profiles of methomyl from methomyl-loaded nanocapsules in an aqueous solution at pH 6.0 were shown to be diffusion controlled with a half-release time (t_1/2) of 36.3–69.5 h from different samples. The shell cross-linking and its degree of cross-linking are assumed to be responsible for this diffusion behavior. The insecticidal activity test in laboratory showed that the control efficacy of methomyl-loaded nanocapsules against the armyworm larvae was significantly superior to the original. The relative control efficacy still maintained 100% over 7 days.