Permeability Interplay Research Articles

Solubility-permeability interplay of hydrotropic solubilization of piroxicam

Objectives In this research paper, an investigation has been made to assess the simultaneous effect of a solubility enhancement approach, i.e., hydrotropy on the solubility and apparent permeability of piroxicam. The solubility of piroxicam (PRX) a BCS (biopharmaceutics classification system) class II drug has been increased using a mixed hydrotropy approach. This study is based on identifying the pattern of solubility-permeability interplay and confirming whether every solubility gain results in a concomitant decrease in permeability or permeability remains unaffected. Method Solid dispersions of PRX were formulated using two hydrotropes, viz., sodium benzoate (SB) and piperazine (PP) by solvent evaporation method. A comprehensive 32factorial design was employed to study the effect of hydrotropes on the solubility and permeability of PRX. Subsequently, PRX tablets containing these solid dispersions were formulated and evaluated. Key findings SB and PP displayed a significant increase in the solubility of PRX ranging from 0.99 to 2.21 mg/mL for F1–F9 batches attributed to the synergistic effect of hydrotropes. However, there is a reduction in PRX permeability with increasing hydrotrope levels. The decline in permeability was notably less pronounced compared to the simultaneous rise in aqueous solubility of PRX. Conclusion An evident tradeoff between permeability and solubility emerged through the mixed hydrotropic solubilization for PRX. As PRX has generally higher intrinsic permeability, it has been assumed that this permeability loss will not affect the overall absorption of PRX. However, it may affect the absorption of drugs with limited permeability. Therefore, solubility permeability interplay should be investigated during solubility enhancement.

MHD Casson Fluid Flow in Stagnation-Point over an Inclined Porous Surface

Motivated by the need to comprehend and optimize complex fluid flow phenomena in various engineering and industrial applications, this paper investigates the magnetohydrodynamic (MHD) Casson fluid flow characteristics in the vicinity of a stagnation point over an inclined porous surface. The study addresses the interplay of permeability, viscous dissipation, buoyancy, and volumetric heat source, chemical reaction of the diffusion species, thermal slip, and obliqueness at the bounding surface. The governing equations are transformed into a dimensionless form using appropriate similarity transformations. The resulting nonlinear ordinary differential equations are solved numerically using the fourth-order Runge-Kutta method, coupled with the shooting technique as coded into the bvp4c solver of MATLAB 2021a. Findings from this study show that instability arises due to reduced velocity at low permeability, and Biot number enhances the Newtonian cooling at the surface, a requirement for the design of heat exchangers.

The Interplay of Permeability, Metabolism, Transporters, and Dosing in Determining the Dynamics of the Tissue/Plasma Partition Coefficient and Volume of Distribution-A Theoretical Investigation Using Permeability-Limited, Physiologically Based Pharmacokinetic Modeling.

A permeability-limited physiologically based pharmacokinetic (PBPK) model featuring four subcompartments (corresponding to the intracellular and extracellular water of the tissue, the residual plasma, and blood cells) for each tissue has been developed in MATLAB/SimBiology and applied to various what-if scenario simulations. This model allowed us to explore the complex interplay of passive permeability, metabolism in tissue or residual blood, active uptake or efflux transporters, and different dosing routes (intravenous (IV) or oral (PO)) in determining the dynamics of the tissue/plasma partition coefficient (Kp) and volume of distribution (Vd) within a realistic pseudo-steady state. Based on the modeling exercise, the permeability, metabolism, and transporters demonstrated significant effects on the dynamics of the Kp and Vd for IV bolus administration and PO fast absorption, but these effects were not as pronounced for IV infusion or PO slow absorption. Especially for low-permeability compounds, uptake transporters were found to increase both the Kp and Vd at the pseudo-steady state (Vdss), while efflux transporters had the opposite effect of decreasing the Kp and Vdss. For IV bolus administration and PO fast absorption, increasing tissue metabolism was predicted to elevate the Kp and Vdss, which contrasted with the traditional derivation from the steady-state perfusion-limited PBPK model. Moreover, metabolism in the residual blood had more impact on the Kp and Vdss compared to metabolism in tissue. Due to its ability to offer a more realistic description of tissue dynamics, the permeability-limited PBPK model is expected to gain broader acceptance in describing clinical PK and observed Kp and Vdss, even for certain small molecules like cyclosporine, which are currently treated as perfusion-limited in commercial PBPK platforms.

Improvement in Solubility-Permeability Interplay of Psoralens from Brosimum gaudichaudii Plant Extract upon Complexation with Hydroxypropyl-β-cyclodextrin.

Psoralen (PSO) and 5-methoxypsoralen (5-MOP) are widely used drugs in oral photochemotherapy against vitiligo and major bioactive components of root bark extract of Brosimum gaudichaudii Trécul (EBGT), previously standardized by LC-MS. However, the exceptionally low water solubility of these psoralens can cause incomplete and variable bioavailability limiting their applications and patient adherence to treatment. Therefore, the purpose of this work was to investigate the effects of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) inclusion complex on the solubility and jejunal permeability of PSO and 5-MOP from EBGT. Characterization of inclusion complexes were evaluated by current methods in nuclear magnetic resonance studies on aqueous solution, Fourier transform infrared spectroscopy, thermal analysis, and scanning electron microscopy in solid state. Ex vivo rat jejunal permeability was also investigated and compared for both pure psoralens and plant extract formulation over a wide HP-β-CD concentration range (2.5 to 70 mM). Phase solubility studies of the PSO- and 5-MOP-HP-β-CD inclusion complex showed 1:1 inclusion complex formation with small stability constants (Kc < 500 M−1). PSO and 5-MOP permeability rate decreased after adding HP-β-CD by 6- and 4-fold for pure standards and EBGT markers, respectively. Nevertheless, the complexation with HP-β-CD significantly improved solubility of PSO (until 10-fold) and 5-MOP (until 31-fold). As a result, the permeability drop could be overcome by solubility augmentation, implying that the HP-β-CD inclusion complexes with PSO, 5-MOP, or EBGT can be a valuable tool for designing and developing novel oral drug product formulation containing these psoralens for the treatment of vitiligo.

Ethanol Based Formulations and the Solubility- Permeability Interplay; does Ethanol Increase the Intestinal Permeability?

Ethanol Based Formulations and the Solubility- Permeability Interplay; does Ethanol Increase the Intestinal Permeability?

Dose-Dependent Solubility-Permeability Interplay for Poorly Soluble Drugs under Non-Sink Conditions.

We investigated the solubility–permeability interplay using a solubilizer additive under non-sink conditions. Sodium lauryl sulfate (SLS) was used as a solubilizer additive. The solubility and permeability of two poorly soluble drugs at various doses, with or without SLS, were evaluated by flux measurements. The total permeated amount of griseofulvin, which has high permeability, increased by the addition of SLS. On the other hand, triamcinolone, which has low permeability, showed an almost constant rate of permeation regardless of the SLS addition. The total permeated amount of griseofulvin increased by about 20–30% when the dose amount exceeded its solubility, whereas its concentration in the donor chamber remained almost constant. However, the total permeated amount of triamcinolone was almost constant regardless of dose amount. These results suggest that the permeability of the unstirred water layer (UWL) may be affected by SLS and solid drugs for high-permeable drugs. The effect of solid drugs could be explained by a reduction in the apparent UWL thickness. For the appropriate evaluation of absorption, it would be essential to consider these effects.

Permeability and Line-Tension-Dependent Response of Polyunsaturated Membranes to Osmotic Stresses

The lipidome of plant plasma membranes—enriched in cellular phospholipids containing at least one polyunsaturated fatty acid tail and a variety of phytosterols and phytosphingolipids—is adapted to significant abiotic stresses. But how mesoscale membrane properties of these membranes such as permeability and deformability, which arise from their unique molecular compositions and corresponding lateral organization, facilitate response to global mechanical stresses is largely unknown. Here, using giant vesicles reconstituting mixtures of polyunsaturated lipids (soy phosphatidylcholine), glucosylceramide, and sitosterol common to plant membranes, we find that the membranes adopt “janus-like” domain morphologies and display anomalous solute permeabilities. The former textures the membrane with a single sterol-glucosylceramide-enriched, liquid-ordered domain separated from a liquid-disordered phase consisting primarily of soy phosphatidylcholine. When subject to osmotic downshifts, the giant unilamellar vesicles (GUVs) respond by transiently producing well-known swell-burst cycles. In each cycle, the influx of water swells the GUV, rendering the membrane tense. Subsequent rupture of the membrane through transient poration, which localizes in the liquid-disordered phase or at the domain boundaries, reduces the osmotic stress by expelling some of the excess osmolytes (and solvent) before sealing. When subject to abrupt hypertonic stress, they deform by nucleating buds at the domain phase boundaries. Remarkably, this incipient vesiculation is reversed in a statistically significant fraction of GUVs because of the interplay with solute permeation timescales, which render osmotic stresses short-lived. This, then, suggests a novel control mechanism in which an interplay of permeability and deformability regulates osmotically induced membrane deformation and limits vesiculation-induced loss of membrane material. Interestingly, recapitulation of such dynamic morphological reconfigurability—switching between budded and nonbudded morphologies—due to the interplay of membrane permeability, which temporally reverses the osmotic gradient, and domain boundaries, which select modes of deformations, might prove valuable in endowing synthetic cells with novel morphological responsiveness.

Influence of hydrophilic polymers addition into cinnarizine–β-cyclodextrin complexes on drug solubility, drug liberation behaviour and drug permeability

The aims of this study were (1) to prepare cinnarizine (CNZ)–β-cyclodextrin (β-CD) complexes by the kneading, co-precipitation and co-evaporation methods with (ternary system) or without (binary system) the addition of two different hydrophilic polymers [hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP)] in their two different grades (HPMC E5-LV or K4M and PVP K-25 or K-30) and (2) to determine the polymers influence on enhancing the CNZ solubility and the in vitro CNZ liberation behaviour or drug permeation characteristics via artificial membrane from the prepared CNZ–β-CD binary and ternary complexes in 0.1 N HCl (pH 1.2). The presence of hydrophilic polymers in ternary complex system did produce irregular-shaped but smooth-surfaced particles while binary complex system (with no polymer addition) did not. The ternary complexes prepared with HPMC K4M, β-CD and CNZ showed higher solubility efficiency value compared to other tested hydrophilic polymers to make ternary complex systems. Consequently, irrespective of the three preparation methods, the ternary complex systems exhibited higher drug libration behaviour in comparison to the binary complex system, physical mixtures and CNZ powder. But because of the possible presence of a solubility and permeability interplay or tradeoff particularly in the binary and ternary complex systems, the CNZ permeation amount in 0.1 N HCl (pH 1.2) via artificial membrane was established to a minimum compared to the CNZ powder. Therefore, the CNZ–β-CD complexes with or without the HPMC and PVP should unequivocally be used with great care by considering the solubility–permeability interplay or tradeoff into account.

Striking the Optimal Solubility-Permeability Balance in Oral Formulation Development for Lipophilic Drugs: Maximizing Carbamazepine Blood Levels.

The purpose of this research was to investigate the performance of cosolvent based solubility-enabling formulations in oral delivery of lipophilic drugs, accounting for the gastrointestinal tract (GIT) luminal solubilization processes, the solubility-permeability interplay, and the overall in vivo systemic absorption. The poorly soluble antiepileptic agent carbamazepine was formulated in three cosolvent-based formulations: 20%, 60%, and 100% PEG-400, and the apparent solubility and rat permeability of the drug in these formulations were evaluated. The performance of the formulations in the dynamic GIT environment was assessed utilizing the biorelevant pH-dilution method. Then, the overall in vivo drug exposure was investigated following oral administration to rats. The three formulations showed dramatic solubility and permeability differences; the 100% PEG-400 provided the highest solubility enhancement and the 20% the poorest, while the exact opposite was evident from the permeability point of view. The dissolution results indicated that the 20% PEG-400 formulation crashes quickly following oral administration, but both the 60% and the 100% PEG-400 formulations allowed full solubilization of the dose throughout the entire GIT-like journey. The best in vivo performing formulation was the 60% PEG-400 (Fsys > 90%), followed by the 100% PEG-400 (Fsys = 76%), and the 20% PEG-400 formulation (Fsys ≈ 60%). In conclusion, this work demonstrates the in vivo solubility-permeability trade-off in oral delivery of lipophilic drugs; when a solubility-enabling formulation is developed, minimal threshold solubility should be targeted, that is just enough to allow solubilization of the drug dose throughout the GIT, while excess solubilizer should be avoided.

Hydrotropic Solubilization of Lipophilic Drugs for Oral Delivery: The Effects of Urea and Nicotinamide on Carbamazepine Solubility-Permeability Interplay.

Hydrotropy refers to increasing the water solubility of otherwise poorly soluble compound by the presence of small organic molecules. While it can certainly increase the apparent solubility of a lipophilic drug, the effect of hydrotropy on the drugs’ permeation through the intestinal membrane has not been studied. The purpose of this work was to investigate the solubility–permeability interplay when using hydrotropic drug solubilization. The concentration-dependent effects of the commonly used hydrotropes urea and nicotinamide, on the solubility and the permeability of the lipophilic antiepileptic drug carbamazepine were studied. Then, the solubility–permeability interplay was mathematically modeled, and was compared to the experimental data. Both hydrotropes allowed significant concentration-dependent carbamazepine solubility increase (up to ∼30-fold). A concomitant permeability decrease was evident both in vitro and in vivo (∼17-fold for nicotinamide and ∼9-fold for urea), revealing a solubility–permeability tradeoff when using hydrotropic drug solubilization. A relatively simplified simulation approach based on proportional opposite correlation between the solubility increase and the permeability decrease at a given hydrotrope concentration allowed excellent prediction of the overall solubility–permeability tradeoff. In conclusion, when using hydrotropic drug solubilization it is prudent to not focus solely on solubility, but to account for the permeability as well; achieving optimal solubility–permeability balance may promote the overall goal of the formulation to maximize oral drug exposure.

Head-To-Head Comparison of Different Solubility-Enabling Formulations of Etoposide and Their Consequent Solubility–Permeability Interplay

The purpose of this study was to conduct a head-to-head comparison of different solubility-enabling formulations, and their consequent solubility-permeability interplay. The low-solubility anticancer drug etoposide was formulated in several strengths of four solubility-enabling formulations: hydroxypropyl-β-cyclodextrin, the cosolvent polyethylene glycol 400 (PEG-400), the surfactant sodium lauryl sulfate, and an amorphous solid dispersion formulation. The ability of these formulations to increase the solubility of etoposide was investigated, followed by permeability studies using the parallel artificial membrane permeability assay (PAMPA) and examination of the consequent solubility-permeability interplay. All formulations significantly increased etoposide's apparent solubility. The cyclodextrin-, surfactant-, and cosolvent-based formulations resulted in a concomitant decreased permeability that could be modeled directly from the proportional increase in the apparent solubility. On the contrary, etoposide permeability remained constant when using the ASD formulation, irrespective of the increased apparent solubility provided by the formulation. In conclusion, supersaturation resulting from the amorphous form overcomes the solubility-permeability tradeoff associated with other formulation techniques. Accounting for the solubility-permeability interplay may allow to develop better solubility-enabling formulations, thereby maximizing the overall absorption of lipophilic orally administered drugs.

The use of captisol (SBE7-β-CD) in oral solubility-enabling formulations: Comparison to HPβCD and the solubility–permeability interplay

The aim of this research was to study the interaction of sulfobutyl ether7 β-cyclodextrin (captisol) and 2-hydroxypropyl-β-cyclodextrin (HPβCD) with the poorly soluble antiarrhythmic drug amiodarone, and to investigate the consequent solubility–permeability interplay. Phase-solubility studies of amiodarone with the two cyclodextrins, followed by PAMPA and rat intestinal permeability experiments, were carried out, and the solubility–permeability interplay was then illustrated as a function of increasing cyclodextrin content. Equimolar levels of captisol allowed ∼10-fold higher amiodarone solubility than HPβCD, as well as binding constant. With both captisol and HPβCD, decreased in vitro and in vivo amiodarone apparent permeability was evident with increasing CD levels and increased apparent solubility. A theoretical model assuming direct proportionality between the apparent solubility increase allowed by the CD and permeability decrease was able to accurately predict the solubility–permeability tradeoff as a function of CD levels. In conclusion, the addition of ionic interactions (e.g. amiodarone–captisol) to hydrophobic interactions of the inclusion complex formation may result in synergic effect on solubilization; however, it is not merely the solubility that should be examined when formulating an oral poorly soluble compound, but the solubility–permeability balance, in order to maximize the overall drug exposure.

Gastrointestinal behavior of nano- and microsized fenofibrate: In vivo evaluation in man and in vitro simulation by assessment of the permeation potential

IntroductionThe purpose of this study was (i) to evaluate the gastrointestinal behavior of micro- and nanosized fenofibrate in humans and (ii) to develop a simple yet qualitatively predictive in vitro setup that simulates the observed absorption-determining factors. Materials and methodsCommercially available micro- and nanoparticles of fenofibrate (Lipanthyl® and Lipanthylnano®, respectively) were administered orally to five healthy volunteers in fasting and postprandial conditions. Intraluminal and systemic drug concentrations were determined as reference data for the development of a predictive in vitro setup. To capture the observed solubility/permeability interplay, in vitro dissolution testing was performed in the presence of a permeation bag with sink conditions. ResultsIn fasting conditions, intake of nanosized fenofibrate generated increased duodenal concentrations compared to microsized fenofibrate, which was reflected in an improved systemic exposure. In postprandial conditions, duodenal concentrations were greatly enhanced for both formulations, however without an accompanying increase in systemic exposure. It appeared that micellar encapsulation of the highly lipohilic fenofibrate limited its potential to permeate from fed state intestinal fluids. To capture these in vivo observations in an in vitro setup, classic dissolution testing was combined with permeation assessment into a permeation bag with sink conditions. In case of fasting conditions, the dissolution/permeation approach allowed for an improved discriminative power between micro- and nanosized fenofibrate by better simulating the dynamic interplay of dissolution and absorption. In case of postprandial conditions, the observed solubility–permeability interplay could be simulated using the dissolution/permeation approach in combination with biorelevant media (FeSSGFFortimel and FeSSIF-V2) to mimic micellar entrapment and reduced permeation potential of fenofibrate. ConclusionFor the first time, reduced permeation of a lipophilic drug despite increased intraluminal concentrations, was demonstrated in humans. Dissolution testing using biorelevant media in combination with permeation assessment into a sink permeation bag appeared to be a simple yet pragmatic approach to capture this solubility–permeability interplay in early formulation evaluation.

The Interplay of Permeability, Drainage Height, Capillarity, and Solvent Type on Diffusion and Convective Dispersion in the Vapex Process: A Critical Review

Despite numerous studies on various aspects of the Vapex process, diffusion and convective dispersion phenomena are of a particular interest. The lack of knowledge in this area has resulted in significant uncertainty in design of this process. This paper assimilates and presents a review on the effects of drainage height, permeability, solvent type, and capillarity on mass transfer phenomena in the Vapex process. Due to the scarcity of phase behavior data and variety of adapted experimental approaches in literature, Vapex number was used to investigate the interplay of studied parameters on the efficiency of mass transfer phenomena in Vapex process.

The interaction of nifedipine with selected cyclodextrins and the subsequent solubility–permeability trade-off

The purpose of this study was to investigate the interaction of 2-hydroxypropyl-β-cyclodextrin (HPβCD) and 2,6-dimethyl-β-cyclodextrin (DMβCD) with the lipophilic drug nifedipine and to investigate the subsequent solubility–permeability interplay. Solubility curves of nifedipine with HPβCD and DMβCD in MES buffer were evaluated using phase solubility methods. Then, the apparent permeability of nifedipine was investigated as a function of increasing HPβCD/DMβCD concentration in the hexadecane-based PAMPA model. The interaction with nifedipine was CD dependent; significantly higher stability constant was obtained for DMβCD in comparison with HPβCD. Moreover, nifedipine displays different type of interaction with these CDs; a 1:1 stoichiometric inclusion complex was apparent with HPβCD, while 1:2 stoichiometry was apparent for DMβCD. In all cases, decreased apparent intestinal permeability of nifedipine as a function of increasing CD level and nifedipine apparent solubility was obtained. A quasi-equilibrium mass transport analysis was developed to explain this solubility–permeability interplay; the model enabled excellent quantitative prediction of nifedipine’s permeability as a function of CD concentrations. This work demonstrates that when using CDs in solubility-enabling formulations, a trade-off exists between solubility increase and permeability decrease that must not be overlooked. This trade-off was found to be independent of the type of CD–drug interaction. The transport model presented here can aid in striking the appropriate solubility–permeability balance in order to achieve optimal overall absorption.

A Win–Win Solution in Oral Delivery of Lipophilic Drugs: Supersaturation via Amorphous Solid Dispersions Increases Apparent Solubility without Sacrifice of Intestinal Membrane Permeability

Recently, we have revealed a trade-off between solubility increase and permeability decrease when solubility-enabling oral formulations are employed. We have shown this trade-off phenomenon to be ubiquitous, and to exist whenever the aqueous solubility is increased via solubilizing excipients, regardless if the mechanism involves decreased free fraction (cyclodextrins complexation, surfactant micellization) or simple cosolvent solubilization. Discovering a way to increase drug solubility without concomitant decreased permeability represents a major advancement in oral delivery of lipophilic drugs and is the goal of this work. For this purpose, we sought to elucidate the solubility-permeability interplay when increased apparent solubility is obtained via supersaturation from an amorphous solid dispersion (ASD) formulation. A spray-dried ASD of the lipophilic drug progesterone was prepared in the hydrophilic polymer hydroxypropyl methylcellulose acetate succinate (HPMC-AS), which enabled supersaturation up to 4× the crystalline drug's aqueous solubility (8 μg/mL). The apparent permeability of progesterone from the ASD in HPMC-AS was then measured as a function of increasing apparent solubility (supersaturation) in the PAMPA and rat intestinal perfusion models. In contrast to previous cases in which apparent solubility increases via cyclodextrins, surfactants, and cosolvents resulted in decreased apparent permeability, supersaturation via ASD resulted in no decrease in apparent permeability with increasing apparent solubility. As a result, overall flux increased markedly with increasing apparent solubility via ASD as compared to the other formulation approaches. This work demonstrates that supersaturation via ASDs has a subtle yet powerful advantage over other solubility-enabling formulation approaches. That is, increased apparent solubility may be achieved without the expense of apparent intestinal membrane permeability. Thus, supersaturation via ASDs presents a markedly increased opportunity to maximize overall oral drug absorption.

Predicting the solubility–permeability interplay when using cyclodextrins in solubility-enabling formulations: Model validation

Although the extraordinary solubility advantage afforded by cyclodextrins has led to their widespread use as pharmaceutical solubilizers, several reports have emerged that cyclodextrins may also reduce the apparent permeability of the drug. With the purpose to investigate this solubility–permeability interplay, we have recently developed a mathematical mass transport model that quantitatively explains the impact of molecular complexation on the intestinal permeability. This model enabled excellent quantitative prediction of progesterone Peff as a function of HPβCD concentrations in several experimental methods. The purpose of the present study was to challenge the predictive capabilities of this mathematical model, assessing whether the model allows the prediction of literature permeability data, as a model validation method. The mass-transport model was applied to carbamazepine and hydrocortisone, and the predicted permeability (Peff, Pm and Paq) vs. HPβCD concentration were plotted. Excellent agreement was obtained between literature experimental permeability and the predicted Peff values for both compounds at all of the HPβCD concentrations tested. The presented validated model that considers the opposing effects of the formulation on the solubility and the permeability, can lead to a more efficient and intelligent use of molecular complexation strategies; the formulator will be able to a priori strike the optimal solubility–permeability balance to maximize and facilitate the overall oral drug absorption.

The Solubility–Permeability Interplay and Its Implications in Formulation Design and Development for Poorly Soluble Drugs

While each of the two key parameters of oral drug absorption, the solubility and the permeability, has been comprehensively studied separately, the relationship and interplay between the two have been largely ignored. For instance, when formulating a low-solubility drug using various solubilization techniques: what are we doing to the apparent permeability when we increase the solubility? Permeability is equal to the drug's diffusion coefficient through the membrane times the membrane/aqueous partition coefficient divided by the membrane thickness. The direct correlation between the intestinal permeability and the membrane/aqueous partitioning, which in turn is dependent on the drug's apparent solubility in the GI milieu, suggests that the solubility and the permeability are closely associated, exhibiting a certain interplay between them, and the current view of treating the one irrespectively of the other may not be sufficient. In this paper, we describe the research that has been done thus far, and present new data, to shed light on this solubility-permeability interplay. It has been shown that decreased apparent permeability accompanies the solubility increase when using different solubilization methods. Overall, the weight of the evidence indicates that the solubility-permeability interplay cannot be ignored when using solubility-enabling formulations; looking solely at the solubility enhancement that the formulation enables may be misleading with regards to predicting the resulting absorption, and hence, the solubility-permeability interplay must be taken into account to strike the optimal solubility-permeability balance, in order to maximize the overall absorption.

Accounting for the solubility–permeability interplay in oral formulation development for poor water solubility drugs: The effect of PEG-400 on carbamazepine absorption

The purpose of this paper was to study the solubility–permeability interplay in formulation development for oral administration of poor aqueous solubility drugs. The apparent solubility of the lipophilic drug carbamazepine was measured in systems containing various levels of the co-solvent PEG-400. The corresponding permeability was then measured in the PAMPA assay and in the rat jejunal perfusion model. Thermodynamic activity was maintained equivalent in all permeability studies (50% saturation). PEG-400 increased carbamazepine solubility in a concentration-dependent fashion. Decreased carbamazepine intestinal permeability with increased apparent solubility was observed in both PAMPA and rat perfusion models. Additionally, we have shown that the intestinal absorption of carbamazepine is membrane-controlled, with essentially no effective barrier function of the unstirred water layer. A mass transport analysis was employed to describe the solubility–permeability interplay. It was shown that the increased solubility in the aqueous GI milieu reduced the apparent membrane/aqueous partitioning, thereby reducing the driving force for membrane permeability. The model enabled excellent quantitative prediction of the effective permeability as a function of the solubility. In conclusion, a direct tradeoff between solubility increase and permeability decrease has been shown, which has to be accounted for when developing oral formulation for lipophilic drugs.

The Solubility–Permeability Interplay: Mechanistic Modeling and Predictive Application of the Impact of Micellar Solubilization on Intestinal Permeation

Surfactants are routinely employed to increase the apparent aqueous solubility of poorly soluble drugs. Yet the impact of micellar solubilization on the intestinal membrane permeability of a lipophilic drug is often overlooked and poorly understood. In this work, the interplay between the apparent solubility increase and intestinal membrane permeability decrease that exists when surfactants are used as drug solubility enhancers is described. A quasi-equilibrium mechanistic mass transport analysis was developed and employed to describe the effect of micellar solubilization by sodium taurocholate (STC) and sodium lauryl sulfate (SLS) on the intestinal membrane permeability of the lipophilic drug progesterone. The model considers the effects of micellar solubilization on both the membrane permeability (P(m)) and the unstirred water layer (UWL) permeability (P(aq)), to predict the overall effective permeability (P(eff)) dependence on surfactant concentration (C(S)). The analysis reveals that (1) the effective UWL thickness (h(aq)) quickly decreases with increasing C(S) above the critical micelle concentration (CMC), such that P(aq) markedly increases with increasing C(S); (2) the free fraction of drug available for membrane permeation decreases with increasing C(S) above CMC, such that P(m) decreases with increasing C(S); and (3) P(aq) increases and P(m) decreases with increasing C(S) above CMC, consequently the UWL is effectively shorted out and the overall P(eff) tends toward membrane control with increasing C(S). The model enabled excellent quantitative prediction of the progesterone P(eff) as a function of C(S) in the rat jejunal perfusion model. This work demonstrates that a trade-off exists between micellar apparent solubility increase and permeability decrease that must be taken into account to strike the optimal solubility-permeability balance. The model presented in this work offers the formulation scientist a simple method for a priori prediction of this interplay, in order to maximize the overall oral absorption.