Ionic Drugs Research Articles

Predicting the solubility enhancement of amorphous drugs and related phenomena using basic thermodynamic principles and semi-empirical kinetic models.

The accurate prediction of the solubility enhancement offered by neat amorphous drugs and amorphous solid dispersions, over their crystalline (API) counterparts, has been discussed in several landmark works dating back at least two decades. Against this backdrop, an assessment of the current state-of-the-art for rigorously, yet simply (circumventing computational methods), determining the amorphous:crystalline solubility ratio based on thermo-analytical quantities is presented herein. Included in this work is a brief survey of the literature together with a discussion of the advantages and shortcomings of some of the most popular approaches, to-date. While the focus is on neat amorphous drugs, both before and after moisture sorption, the methodology presented is readily extended to more complex (e.g. ternary) systems that form a single, homogeneous phase. Six key questions are addressed in the context of how to most accurately determine the amorphous:crystalline solubility ratio: (1) How is the lattice energy of the crystalline phase assessed? (2) What is the role of heat capacity? (3) How does the pKa impact the solubility ratio prediction (for ionizable drugs)? (4) How does one incorporate the effects of moisture sorption on the amorphous phase? (5) How might one characterize (predict) the rate of drug recrystallization under various conditions (since the duration of the solubility enhancement is a kinetic phenomenon)? (6) What is the best approach for linking the (loss in) solubility enhancement to the Tg-lowering of the amorphous drug (by water) and vice-versa? In addressing these questions, this work aims to put forth a standardized methodology for determining the amorphous solubility enhancement with improved accuracy.

Effects of phosphate on drug solubility behavior of mixture ibuprofen and lidocaine

Drug solubility is an important characteristic affecting its bioavailability. The properties of ionic drugs affect their sensitivity to buffer composition. We aimed to elucidate the variations in ibuprofen solubility due to different buffers and buffer concentrations. We also examined the intermolecular interaction between IBP and lidocaine (LDC) in the presence or absence of phosphate ion to determine whether phosphate in buffer modifies IBP hydration and LDC hydrophobic hydration. The IBP/LDC mixture formed a complex in phosphate buffer, as confirmed by van't Hoff plot and diffusion-ordered NMR spectroscopy, where dissolving behavior changed from endothermic to an exothermic process. This behavior was only achieved in the presence of phosphate ion. We also examined the dependence of a drug’s solubility on the solubility of other drugs. Phosphate ion can greatly affect drug solubility behavior. This knowledge gives us to ensure comparative assessment that is suitable for the Electrolyte environment of patients.

Managing efficacy and toxicity of drugs: Targeted delivery and excretion

Medicine is a natural companion of mankind in the present era for mere survival from the deadly diseases in ever-increasing polluted environments. Hence, in recent years, major focus of pharmaceutical, medicinal and biophysical research has been navigated in exploring and developing new and simple avenues to enhance the efficacy of the administered drugs on one hand and to get rid of, or at least reduce, the toxic side effects of the excess drugs accumulated in human body on the other. A potential approach to amplify the efficacy of the administered drug is to develop proficient targeted drug delivery systems (DDSs). This review provides an essence of some newly developed simple but prospective strategies on enhancing the efficacy of drugs/bioactive molecules exploiting various drug delivery systems like micelles, cyclodextrins, liposomes etc. to serve the purpose of targeted delivery towards DNA, by endogenous and/or exogenous means. Improved bio-availability and solubilization of ionic drugs within the less polar target regions from the bulk aqueous phase has also been achieved through the introduction of some physiologically permissible salts. In the other context, in vitro and in vivo studies demonstrate a simple technique for easy removal of the excess adsorbed drug molecules from the cell membranes/lipid bilayers by exploiting health-amiable supramolecular assemblies.In this review, we summarize the recent experimental findings, mostly from our lab, encompassing the development of simple biocompatible methods to enhance the benevolent role of drugs through their safe, effective and convenient administration. It also presents easy and effective means to remove the excess adsorbed drugs from human body to diminish their malign effects. These prospective approaches of drug delivery and excretion of drug molecules have promising roles to play from both physicochemical and pharmaceutical perspectives, ensuring enhanced bioavailability of drugs as well as disposing of drug-induced adverse side effects.

Delivery of ionic molecules to anterior chamber by iontophoretic contact lenses

Ophthalmic delivery via iontophoresis is currently achieved by placing an electrode on the cornea with a counter electrode on the ear or forehead. Here we test the feasibility of placing both electrodes diametrically opposite on a contact lens to create field gradients to transport ionic drugs into the cornea.Commercial lenses loaded with nile blue and fluorescein as hydrophobic and hydrophilic drug analogs, respectively were placed on cadaver rabbit eyes. Electric field gradients were created by placing cathode and anode on the lens diametrically opposite to each other. The incorporation of an electric field (0.125 m–0.250 mA), showed an increased uptake of nile blue and the quantity was a function of the duration of the electric field and the amount of applied current. Similar increases in flux were observed for fluorescein. Confocal fluorescence imaging also shows increased penetration of the dyes in presence of the field. An equivalent circuit model suggests that the field gradients are much stronger in the direction perpendicular to the cornea, which results is minimal short circuiting of current through the tear film. The incorporation of an electric field into a lens could be a less invasive and more effective approach to achieve ophthalmic drug delivery via iontophoresis.

Mass Transport Analysis of Bicarbonate Buffer: Effect of the CO2-H2CO3 Hydration-Dehydration Kinetics in the Fluid Boundary Layer and the Apparent Effective p Ka Controlling Dissolution of Acids and Bases.

The main buffering system influencing ionizable drug dissolution in the human intestinal fluid is bicarbonate-based; however, it is rarely used in routine pharmaceutical practice due to the volatility of dissolved CO2. The typical pharmaceutical buffers used fail to capture the unique aspects of the hydration-dehydration kinetics of the bicarbonate-CO2 system. In particular, CO2 is involved in a reversible interconversion with carbonic acid (H2CO3), which is the actual conjugate acid of the system, as follows CO2 + H2O ⇌ H2CO3. In contrast to ionization reactions, this interconversion does not equilibrate very rapidly compared to the diffusional processes through a typical fluid diffusion boundary layer at a solid-liquid interface. In this report, a mathematical mass transport analysis was developed for ionizable drug dissolution in bicarbonate using the rules of conservation of mass and electric charge in addition to accounting for the diffusional times and reaction rate constants of the CO2-H2CO3 interconversion. This model, which includes both the hydration reaction rate and dehydration reaction rate, we called the "reversible non-equilibrium" (RNE) model. The predictions made by this RNE approach for ionizable drug dissolution rates were compared to the experimental data generated by an intrinsic dissolution method for three ionizable drugs, indomethacin, ibuprofen, and haloperidol. The results demonstrate the superiority of predictions for the RNE approach compared to the predictions of a model assuming equilibrium between CO2 and H2CO3, as well as models ignoring reactions. The analysis also shows that bicarbonate buffer can be viewed as having an effective p Ka in the boundary layer that is different from that in bulk and is hydrodynamics-dependent.

Contact Lens Based Drug Delivery to the Posterior Segment Via Iontophoresis in Cadaver Rabbit Eyes.

A drug loaded contact lens combined with electrodes positioned diametrically opposite and beyond the limbus can potentially deliver ionic drugs directly to the vitreous. Commercial lenses are loaded with nile blue or fluorescein as the drug analogs and placed on cadaver rabbit eyes. Electrodes (19.6mm2) are placed atop at opposite sides of the sclera to apply a constant current (0.125-0.250mA) for 1-2h. COMSOL simulations are conducted to determine the field distribution and the potential drop across various tissue layers and equivalent circuit model is developed to calculate the electrophoretic velocity and estimate the drug flux. The device delivered both hydrophobic and hydrophilic dyes to the tissue. The amount of fluorescein delivered to the vitreous directly correlated with the applied current and time duration. The electrophoretic mobility from the experimental data agreed with the model estimates. Confocal microscopy showed that nile blue penetrated through the conjunctiva-sclera barrier to reach the retina showing that the electric field can transport molecules through the ocular tissue and into the vitreous. The ex vivo model neglects transport into flowing capillaries in the choroid. However, the time scale for electrophoretic transport across the choroid was found to be 550-1300 fold shorter than that for uptake into the choroidal capillaries. Incorporation of an electric field with multiple electrodes on a single lens can effectively deliver ionic drugs to the posterior region at levels comparable to current methods with the benefits of being safer and less invasive.

Choline based polymethacrylate matrix with pharmaceutical cations as co-delivery system for antibacterial and anti-inflammatory combined therapy

Anionic drugs, i.e. salicylate (Sal−) and sulfacetamide (Sfc−) were chosen as counterions in trimethylammonium based poly(meth)acrylates. These ionic systems with amphiphilic properties were used to form polymeric systems for dual drug delivery by loading of nonionic pharmaceutics like immunosuppressant quercetin (QUE), anti-inflammatory indomethacin (IMC) and antibiotic erythromycin (ERY). The latter one was loaded with high efficiency (>60%), whereas poorer loading efficiency was obtained for aromatic compounds (<10%) because of strong repulsing effect with ionic moieties in polymer matrix. Coordinating and polar properties of anions as the additional factors in drug-polymer affinity can be applied to adjust the drug loading and release. The polymer particles resulted in aqueous solutions were characterized by hydrodynamic diameters (70–430 nm) and zeta potentials (20–65 mV) indicating specific multifactor action/contraction of drug delivery system (DDS) components. The release profiles of both type drugs demonstrated typical diffusion process with burst effect during initial 2 h, and then it slowed down for next 80 h. The release rate of bioactive anions in the dual system was not affected by the presence of nonionic drug showing comparable kinetics profile with the analogical single drug system carrying ionic drug. The most promising Sal-based and ERY-loaded polymer system was able to release ~60% of ionic drug (via exchange with phosphate anions in buffer solution) and ~70% of nonionic drug. The biological studies on the proposed polymeric systems were conducted indicating no toxic activity against human cells (NHDF and BEAS-2B), no gene expression for anti-inflammatory interleukins IL6 and IL8 as well as the antibacterial activity was observed against E. coli.

Controllable Transformation of Aligned ZnO Nanorods to ZIF-8 as Solid-Phase Microextraction Coatings with Tunable Porosity, Polarity, and Conductivity.

While a growing number of solid-phase microextraction (SPME) coatings have been developed, a generalized protocol is still needed to tailor-make SPME coatings with desirable properties for efficient extraction of diverse analytes from sample matrixes. In this work, we developed a versatile approach to prepare SPME coatings with tunable properties by controllable in situ transformation of well-aligned ZNRs into zeolitic imidazolate frameworks-8 (ZIF-8) via reaction with 2-methylimidazole (2-MI). During this process, ZNRs supplied Zn2+ and served as a "hard template" for the in situ growth of well-aligned ZIF-8 with enhanced surface area for adsorption. Because ZNRs and ZIF-8 exhibit markedly different properties, we obtained a series of ZNRs/ZIF-8 hybrid composites, whose morphology, porosity, polarity, and charge transfer resistance can be fine-tuned by simply controlling the concentration of 2-MI. Preparing ZNRs/ZIF-8 SPME coatings with desired properties enabled effective extraction of a wide range of polar and nonpolar compounds including aliphatic hydrocarbons, polycyclic aromatic hydrocarbons, alcohols, phenols, anilines, and ionic drugs.

Improved transdermal permeability of ibuprofen by ionic liquid technology: Correlation between counterion structure and the physicochemical and biological properties

The aim of this study was to explore the feasibility of transdermal delivery of ibuprofen using ionic liquid technology. Ibuprofen, a non-steroidal anti-inflammatory drug, was transformed into nine ionic liquids using aromatic, tetraalkylammonium and tetraalkylphosphonium cationic counterions. Both the free drug and synthesized ionic liquids were fully characterized by X-ray Powder Diffractometry (XRPD) analysis, thermal analysis, Fourier Transform Infrared Spectroscopy (FT-IR) analysis and Nuclear Magnetic Resonance Spectrometer analysis (NMR), and the aqueous solubility at 25 °C as well as the octanol-water partition coefficients (LogP) were measured. To evaluate transdermal potential, in vitro skin permeation testing was carried out via Skin Parallel Artificial Membrane Permeability Assays (Skin PAMPA). In addition, the potential skin toxicity of ionic liquids was evaluated by determining their cytotoxicity against HaCaT cells. All the synthesized ibuprofen ionic liquids showed improved skin permeability comparing with the conventional sodium salt. Specifically, ionic liquids with didecyldimethylammonium and tetrahexylammonium counterions were significantly more permeable through artificial skin membrane than the free form of ibuprofen. Conductivity test and 2D NMR nuclear Overhauser effect (NOE) techniques corroborated that ionic liquids with stronger intermolecular intermolecular interaction and higher degree of ion association in aqueous environment crossed the artificial skin membrane more rapidly and efficiently. Taken together, ionic liquids technology could be a versatile platform to turn the physicochemical and biological properties of ionizable drugs and facilitate their transdermal delivery.

The Use of Molecular Descriptors To Model Pharmaceutical Uptake by a Fish Primary Gill Cell Culture Epithelium.

Modeling approaches such as quantitative structure–activity relationships (QSARs) use molecular descriptors to predict the bioavailable properties of a compound in biota. However, these models have mainly been derived based on empirical data for lipophilic neutral compounds and may not predict the uptake of ionizable compounds. The majority of pharmaceuticals are ionizable, and freshwaters can have a range of pH values that affect speciation. In this study, we assessed the uptake of 10 pharmaceuticals (acetazolamide, beclomethasone, carbamazepine, diclofenac, gemfibrozil, ibuprofen, ketoprofen, norethindrone, propranolol, and warfarin) with differing modes of action and physicochemical properties (pKa, log S, log D, log Kow, molecular weight (MW), and polar surface area (PSA)) by an in vitro primary fish gill cell culture system (FIGCS) for 24 h in artificial freshwater. Principal component analysis (PCA) and partial least-squares (PLS) regression was used to determine the molecular descriptors that influence the uptake rates. Ionizable drugs were taken up by FIGCS; a strong positive correlation was observed between log S and the uptake rate, and a negative correlation was observed between pKa, log D, and MW and the uptake rate. This approach shows that models can be derived on the basis of the physicochemical properties of pharmaceuticals and the use of an in vitro gill system to predict the uptake of other compounds. There is a need for a robust and validated model for gill uptake that could be used in a tiered risk assessment to prioritize compounds for experimental testing.

New Ionic Cu(II) and Co(II) DACH–Flufenamate Conjugate Complexes: Spectroscopic Characterization, Single X–Ray Studies and Cytotoxic Activity on Human Cancer Cell Lines

AbstractNew ionic antitumor drug entities [{Cu(DACH)2(H2O)Cl}.(fluf)], 1 and [{Co(DACH)2(H2O)Cl}.(fluf)], 2 where DACH=1,2–diamminocyclohexane and fluf=flufenamate anion were prepared and characterized by spectroscopic studies and single X–ray crystallography. In order to evaluate the potential of these complexes to act as antitumor drug candidates, in vitro binding studies of 1 and 2 with ct–DNA have been carried out by biophysical methods which revealed electrostatic binding mode of these drug entities with ct–DNA preferably by external surface or groove binding mode contrary to other non–steroidal anti–inflammatory (NSAIDs) drugs which show intercalative binding. Comparative electron paramagnetic resonance (EPR) titrations were performed which revealed that there was no significant change in EPR spectra of complexes upon incubation with ct–DNA implicating that coordination geometry of metal ions does not alter. Validation of antitumor potential of 1 and 2 was done by cytotoxicity experiments against human cancer cell lines by Sulforhodamine B (SRB) assay. Complex 1 was active against all tested cell lines with an exceptionally low GI50 value=2.9 μg/ml against MCF–7 (breast cancer) cell line showing its preferential selectivity. On the contrary, complex 2 showed poor activity against all tested cancer cell lines.

Mass Transport Analysis of the Enhanced Buffer Capacity of the Bicarbonate–CO2 Buffer in a Phase-Heterogenous System: Physiological and Pharmaceutical Significance

The bicarbonate buffer capacity is usually considered in a phase-homogeneous system, at equilibrium, with no CO2 transfer between the liquid buffer phase and another phase. However, typically, an in vitro bicarbonate buffer-based system is a phase-heterogeneous system, as it entails continuously sparging (bubbling) the dissolution medium with CO2 in a gas mixture, at constant ratio, to maintain a constant partial pressure of CO2(g) and CO2(aq) molarity at a prescribed value, with CO2 diffusing freely between the gas and the aqueous phases. The human gastrointestinal tract is also a phase-heterogeneous system, with CO2 diffusing across the mucosal membrane into the mesenteric arterial blood, which serves as a sink for CO2 from the intestinal lumen. In this report, a mass transport analysis of the apparent buffer capacity of a phase-heterogeneous bicarbonate-CO2 system is developed. It is shown that, most significantly, a phase-heterogeneous bicarbonate-CO2 system can have a much higher buffer capacity than a phase-homogeneous system such that the buffer capacity is dependent on the bicarbonate concentration. It is double that of a phase-homogeneous system at the pH = p Ka for a monoprotic buffer at the same concentration. This buffer capacity enhancement increases hyperbolically with pH above the p Ka, thus providing a much stronger buffering to keep the pH in the physiologically neutral range. The buffer capacity will be dependent on the bicarbonate molarity (which in vivo will depend on the bicarbonate secretion rate) and not the pH of the luminal fluid. Further, there is no conjugate acid accumulation as a result of bicarbonate neutralization, since the resulting carbonic acid (H2CO3) rapidly dehydrates producing CO2 and H2O. The mass transport analysis developed in this report is further supported by in vitro experimental results. This enhanced bicarbonate buffer capacity in a phase-heterogeneous system is of physiological significance as well as significant for the dissolution and absorption of ionizable drugs.

The effectiveness of decontamination procedures used in forensic hair analysis

Hair is a mainstream specimen used in forensic toxicology to determine drug use and exposure. However, the interpretation of an analytical hair result can be complicated by the presence of external drug contamination. Decontamination procedures are included in hair analysis methods to remove external contamination, but the capacity of these washes to completely remove contamination for all drugs is controversial. It is evident that there is no consensus on the most effective decontamination procedure, nor can decontamination procedures consistently remove external drug contamination to less than reportable cut-offs for all analytes. ∆9-tetrahydrocannabinol deposited from cannabis smoke is mostly removed by organic solvents, whereas ionizable drugs are more effectively removed by an aqueous wash. Organizations such as the Society of Hair Testing recommend a hair decontamination procedure should include both an organic and aqueous washing step, which is in accordance with the reviewed literature. Studies involving a systematic evaluation of various solvents have shown that the most effective organic solvent was methanol and the most effective aqueous solvent contained sodium dodecyl sulfate detergent. If future systematic studies can demonstrate similar findings, a consensus on the most effective decontamination procedure for forensic hair analysis may be established.

Effect of excipient properties, water activity, and water content on the disproportionation of a pharmaceutical salt

Excipients are crucial components of most pharmaceutical formulations. In the case of a solid oral dosage formulation containing the salt form of a weakly ionizable drug, excipient selection is critical, as some excipients are known to cause salt disproportionation (conversion of salt to the free form). Therefore, robust formulation design necessitates an in-depth understanding of the factors impacting salt disproportionation during processing or storage as this can negatively impact product quality and performance. To date, there is an incomplete understanding of key excipient properties influencing salt disproportionation. Specifically, the potential roles of amorphous excipient glass transition temperature and excipient hygroscopicity, if any, on salt disproportionation are still not well understood. Furthermore, the relationship between the compression and the extent of salt disproportionation is an unknown factor. Herein, by utilizing various grades of polyvinylpyrrolidone (PVP), its copolymer, copovidone (PVPVA), and magnesium stearate, a systematic investigation of disproportionation was performed using pioglitazone HCl as a model salt of a weak base. It was observed that there was a poor correlation between excipient hygroscopicity and the rate and extent of disproportionation. However, powder compression into compacts enhanced the rate and extent of disproportionation. This work focused on disproportionation of the salt of a weak base, as basic drugs are more prevalent, however, salts of weak acids may have similar tendencies under relevant conditions. The knowledge gained from this study will help in understanding the role of various excipients with respect to salt disproportionation, paving the way for designing stable salt formulations.

Electrodeless Reverse Electrodialysis Patches as an Ionic Power Source for Active Transdermal Drug Delivery

AbstractReverse electrodialysis (RED) is one of the promising sustainable technologies generating electric power from the mixing energy of two different salt solutions. Most of the reports on the RED systems are focused on scale‐up development and the improvement of maximum power density. However, regarding biocompatible and eco‐friendly natures, the RED system also has a great potential use where low electrical power is necessary, in particular for skin‐wearable biomedical devices. In this work, electronics‐free RED patches are devised as an ionic power source for active transdermal drug delivery. The electrodeless RED patches generate reliable voltages, which are proportional to the number of ion‐exchange membranes and salinity ratios, and successfully facilitate in vitro delivery of ionic drugs through mouse skin without involving any electronic component for the first time; 9, 20, and 36‐fold increases with lidocaine, ketorolac, and risedronate, respectively. Indeed, by using an osteoporosis‐induced mouse model, the RED patch delivery demonstrates powerful in vivo therapeutic effects against the diffusion‐based topical administration. The new ionic power source can allow transport of various types of drugs in the transdermal route and, more importantly, can be used for the operation of other portable biomedical devices.

Investigation of Methylene Blue Release from Functional Polymeric Systems Using Dielectric Analysis.

Methylene blue (MB) is a photosensitizer used in photodynamic therapy (PDT) to treat colorectal cancer tumors and leishmaniasis infection. The clinical efficacy of PDT using MB is dependent on the physicochemical characteristics of the formulation. Bioadhesive thermoresponsive systems containing poloxamer 407 and Carbopol 934P have been proposed as platforms for PDT. However, the effect of MB on the physicochemical properties of these platforms is not fully understood, particularly in light of the MB availability. The aim of this study was to investigate the dielectric characteristics of functional polymeric systems containing MB and their influence on mucoadhesion and drug release. Binary polymeric systems containing different concentrations of poloxamer 407, Carbopol 934P and MB were evaluated as dielectric and mucoadhesive properties, as well as in vitro drug release profile. MB, temperature and polymeric composition influenced the physicochemical properties of the systems. The presence of MB altered the supramolecular structure of the preparations. The mucoadhesive properties of systems were influenced by MB presence and the formulation with the lowest amount of MB displayed faster release. The lower MB concentration in the systems displayed better results in terms of ionic mobility and drug release, and is indicative of a suitable clinical performance.

Method Validation for Equilibrium Solubility and Determination of Temperature Effect on the Ionization Constant and Intrinsic Solubility of Drugs

We performed this study to understand the physicochemical properties of drug-like molecules such as pKa and logS0 (logS) values. The first purpose is to compare pKa and logS0 values obtained using a prediction tool and experimental results. The second purpose is to identify the temperature effect of pKa and logS0 for ionizable drugs at 25ºC and 37ºC. PKa and logS0 of ordinary base compounds were significantly changed by increasing the temperature, but acid and amphoteric compounds were not. The third purpose is to validate the shake-flask method using different buffers and stirring and sedimentation times compared with potentiometric experiments. The equilibrium solubility from the shake-flask method had an excellent consistency with the potentiometric method (CheqSol) for crystalline forms. Additionally, measurement of amorphous compounds, which are poorly soluble and metastable in aqueous solutions, was feasible to determine logS0 (and logS) values using the CheqSol technique.

Applications of Ion Exchange Resin in Oral Drug Delivery Systems

Ion Exchange Resins (IER) are insoluble polymers having styrene divinylbenzene copolymer backbone that contain acidic or basic functional groups and have the ability to exchange counter ions with the surrounding aqueous solutions. From the past many years they have been widely used for purification and softening of water and in chromatographic columns, however recently their use in pharmaceutical industry has gained considerable importance. Due to the physical stability and inert nature of the resins, they can be used as a versatile vehicle to design several modified release dosage forms The ionizable drug is complexed with the resin owing to the property of ion exchange. This resin complex dissociatesin vivo to release the drug. Based on the dissociation strength of the drug from the drug resin complex, various release patterns can be achieved. Many formulation glitches can be circumvented using ion exchange resins such as bitter taste and deliquescence. These resins also aid in enhancing disintegrationand stability of formulation. This review focuses on different types of ion exchange resins, their preparation methods, chemistry, properties, incompatibilities and their application in various oral drug delivery systems as well as highlighting their use as therapeutic agents.

Modeling drug release through stimuli responsive polymer hydrogels

There is a rising interest in stimuli-responsive hydrogels to achieve controlled and self-regulated drug delivery. Stimuli responsive polymer hydrogels with their ability to swell/de-swell under varying pH conditions present themselves as a potential candidate for controlled drug delivery. It is important to develop a mechanistic understanding of the underlying phenomena that will help suggest ways to control the drug release from a polymer hydrogel. We present a mathematical model that couples Nernst–Planck, Poisson and force balance equations to incorporate diffusion of ionic species and drug along with deformation of hydrogel under osmotic pressure. The model can be used to simulate swelling behaviour of the hydrogel along with the kinetics of drug release. It has been validated with published experimental data for swelling of polyhydroxyethyl methacrylate-co-methacrylic acid (pHEMA-co-MA) gels and release kinetics of Phenylpropanolamine from these gels. Effect of formulation parameters such as polymer concentration and cross-linker concentration has also been evaluated. The model can be used to reduce the number of exploratory experiments required during design of a drug delivery system.

Low Buffer Capacity and Alternating Motility along the Human Gastrointestinal Tract: Implications for in Vivo Dissolution and Absorption of Ionizable Drugs.

In this study, we determined the pH and buffer capacity of human gastrointestinal (GI) fluids (aspirated from the stomach, duodenum, proximal jejunum, and mid/distal jejunum) as a function of time, from 37 healthy subjects after oral administration of an 800 mg immediate-release tablet of ibuprofen (reference listed drug; RLD) under typical prescribed bioequivalence (BE) study protocol conditions in both fasted and fed states (simulated by ingestion of a liquid meal). Simultaneously, motility was continuously monitored using water-perfused manometry. The time to appearance of phase III contractions (i.e., housekeeper wave) was monitored following administration of the ibuprofen tablet. Our results clearly demonstrated the dynamic change in pH as a function of time and, most significantly, the extremely low buffer capacity along the GI tract. The buffer capacity on average was 2.26 μmol/mL/ΔpH in fasted state (range: 0.26 and 6.32 μmol/mL/ΔpH) and 2.66 μmol/mL/ΔpH in fed state (range: 0.78 and 5.98 μmol/mL/ΔpH) throughout the entire upper GI tract (stomach, duodenum, and proximal and mid/distal jejunum). The implication of this very low buffer capacity of the human GI tract is profound for the oral delivery of both acidic and basic active pharmaceutical ingredients (APIs). An in vivo predictive dissolution method would require not only a bicarbonate buffer but also, more significantly, a low buffer capacity of dissolution media to reflect in vivo dissolution conditions.