Solubility Of Model Drug Research Articles

An empirical predictive model for determining the aqueous solubility of BCS class IV drugs in amorphous solid dispersions

Context Determining solubility of drugs is laborious and time-consuming process that may not yield meaningful results. Amorphous solid dispersion (ASD) is a widely used solubility enhancement technique. Predictive models could streamline this process and accelerate the development of oral drugs with improved aqueous solubilities. Objective This study aimed to develop a predictive model to estimate the solubility of a compound from the ASDs in polymer matrices. Methods ASDs of model drugs (acetazolamide, chlorothiazide, furosemide, hydrochlorothiazide, sulfamethoxazole) with model polymers (PVP, PVPVA, HPMC E5, Soluplus) and a surfactant (TPGS) were prepared using hotmelt process. The prepared ASDs were characterized using DSC, FTIR, and XRD. The aqueous solubility of the model drugs was determined using shake-flask method. Multiple linear regression was used to develop a predictive model to determine aqueous solubility using the molecular descriptors of the drug and polymer as predictor variables. The model was validated using Leave-One-Out Cross-Validation. Results The ASDs’ drug components were identified as amorphous via DSC and XRD Studies. There were no significant chemical interactions between the model drugs and the polymers based on FTIR studies. The ASDs showed a significant (p < 0.05) improvement in solubility, ranging from a 3-fold to 118-fold, compared with the pure drug. The developed empirical model predicted the solubility of the model drugs from the ASDs containing model polymer matrices with an accuracy greater than 80%. Conclusion The developed empirical model demonstrated robustness and predicted the aqueous solubility of model drugs from the ASDs of model polymer matrices with an accuracy greater than 80%.

Push-Pull Osmotic Pumps Using Crosslinked Hard Gelatin Capsule as a Structural Assembly for Delivery of Drugs with Different Water Solubilities

The aim of this work was to prepare push-pull osmotic pump capsules using crosslinked hard gelatin capsules as a structural assembly for delivery of four model drugs with different water solubilities including diltiazem hydrochloride, propranolol hydrochloride, ambroxol hydrochloride, and paracetamol. A hard gelatin capsule was crosslinked in formaldehyde vapor for 12 h. Then, a push-pull osmotic pump capsule was prepared, and formulation factors were investigated, i.e., the amount and solubility of model drugs, the amount of polyethylene oxide in pull layer, and size of the capsule. Drug release was evaluated to clarify the release characteristic in several release mediums. Results showed that drug release was independent of drug solubility, drug amount, and capsule size. Almost all of the drug release approached Higuchi’s release model. However, ambroxol hydrochloride could not deliver via this device because of its rather high-density drug particle. Reduction of the polyethylene oxide amount resulted in less drug release. Increasing osmolality of the medium reduced drug release. Drug release studies using a medium with digestive enzymes did not alter drug release compared to medium without enzymes. Push-pull osmotic pump capsules prepared from stored crosslinked hard gelatin capsule shells provided reproducible drug release characteristic. This developed push-pull osmotic pump capsule is an alternative osmotic pump device for delivery of drugs with different water solubilities.

Effects of Transport Medium Composition on In vitro Drug Permeation Across Excised Pig Intestinal Tissue

Background:: Knowledge of the permeation characteristics of new chemical entities across biological membranes is essential to drug research and development. Transport medium composition may affect the absorption of compounds during in vitro drug transport testing. To preserve the predictive values of screening tests, the possible influence of transport media on the solubility of model drugs and on the activities of tight junctions and efflux transporter proteins (e.g., Pglycoprotein) must be known. Objective:: The aim of this study was to compare the impact of different transport media on the bidirectional transport of standard compounds, selected from the four classes of the Biopharmaceutical Classification System (BCS), across excised pig intestinal tissue. Methods:: The Sweetana-Grass diffusion apparatus was used for transport studies. Krebs-Ringer bicarbonate (KRB) buffer and simulated intestinal fluids in the fed (FeSSIF) and fasted (FaSSIF) states were used as the three transport media, while the chosen compounds were abacavir (BCS class 1), dapsone (BCS class 2), lamivudine (BCS class 3) and furosemide (BCS class 4). Results:: Abacavir exhibited lower permeability in both the simulated intestinal fluids than in the KRB buffer. Dapsone showed similar permeability in all media. Lamivudine exhibited lower permeability in FaSSIF than in the other two media. Furosemide exhibited improved transport with pronounced efflux in FaSSIF. Conclusion:: Different permeation behaviors were observed for the selected drugs in the respective media, which may have resulted from their different physico-chemical properties, as well as from the effects that dissimilar transport media components had on excised pig intestinal tissue.

Synergistic Computational Modeling Approaches as Team Players in the Game of Solubility Predictions

Several approaches to predict and model drug solubility have been used in the drug discovery and development processes during the last decades. Each of these approaches have their own benefits and place, and are typically used as standalone approaches rather than in concert. The synergistic effects of these are often overlooked, partly due to the need of computational experts to perform the modeling and simulations as well as analyzing the data obtained. Here we provide our views on how these different approaches can be used to retrieve more information on drug solubility, ranging from multivariate data analysis over thermodynamic cycle modeling to molecular dynamics simulations. We are discussing aqueous solubility as well as solubility in more complex mixed solvents and media with colloidal structures present. We conclude that the field of computational pharmaceutics is in its early days but with a bright future ahead. However, education of computational formulators with broad knowledge of modeling and simulation approaches is imperative if computational pharmaceutics is to reach its full potential.

Harmonizing solubility measurement to lower inter-laboratory variance - progress of consortium of biopharmaceutical tools (CoBiTo) in Japan.

The purpose of the present study was to harmonize the protocol of equilibrium solubility measurements for poorly water-soluble drugs to lower inter-laboratory variance. The “mandatory” and “recommended” procedures for the shake-flask method were harmonized based on the knowledge and experiences of each company and information from the literature. The solubility of model drugs was measured by the harmonized protocol (HP) and the non-harmonized proprietary protocol of each company (nonHP). Albendazole, griseofulvin, dipyridamole, and glibenclamide were used as model drugs. When using the nonHP, the solubility values showed large inter-laboratory variance. In contrast, inter-laboratory variance was markedly reduced when using the HP.

The Release Characteristics of Different Model Drugs from Medicated PLGA Microspheres

In this study, four model drugs, i.e., Meloxicam (MEL), Risperidone (RIS), Eprinomectin (EPR), and Bull Serum Albumin (BSA), were encapsulated in PLGA microspheres via solvent evaporation methods. The encapsulation efficiency and in vitro release profiles of different drugs with various water solubilities from medicated PLGA microspheres were investigated. The surface morphologies of microspheres were detected by scanning electron microscope (SEM). The release characteristics of the model drugs from the medicated microspheres were carried out in the phosphate buffer solution (PBS), pH7.4, at 37 °C. Studies found that the water solubility of model drugs had significant influences on their in vitro release profiles and the release rates of four model drugs were in the orders of BSA＞MEL＞RIS＞EPR.

Tailored beads made of dissolved cellulose—Investigation of their drug release properties

In the frame of this work, we have investigated drug entrapping and release abilities of new type of porous cellulose beads (CBs) as a spherical matrix system for drug delivery. For that purpose, CBs prepared with three different methods were used as drug carriers and three compounds, anhydrous theophylline (Thp), riboflavin 5'-phosphate sodium (RSP) and lidocaine hydrochloride monohydrate (LiHCl) were used as model drug substances. The loading procedure was carried out by immersing swollen empty beads into the solutions of different concentrations of model drugs. The morphology of empty and loaded beads was examined using a field emission scanning electron microscopy (FE-SEM). Near-infrared (NIR) imaging was performed to identify the drug distributions on and within the loaded CBs. The drug amount incorporated into CBs was examined spectrophotometrically and in vitro drug release studies were performed to determine the drug release rates. The results of FE-SEM and chemical NIR imaging analyses revealed that incorporated drug were distributed on the surface and but also within the internal structure of the CBs. Physical properties of CBs and solubility of model drugs had effect on loading efficacy. Also, the drug release rates were controlled by solubility of model drugs (diffusion controlled release). In conclusion, CBs from dissolved cellulose show promise in achieving controlled drug delivery.

Synthesis of novel dendrimers having aspartate grafts and their ability to enhance the aqueous solubility of model drugs

In this study, a series of aspartate based dendrimers with different cores were synthesized in a convergent approach and well characterized by NMR and MS techniques. The aqueous solubility of the model drugs (L-Histidine, Naproxen, Methotrexate) was measured in the presence of this kind of dendrimers at room temperature in PBS buffers at pH 6, 7 and 8. Results clearly confirmed that the solubility enhancement was due to presence of dendrimers at different pH compared to their corresponding aqueous solubility at different pH. The results indicated that the aspartate based dendrimers could be considered as an effective supplement of PAMAM dendrimers in solubility enhancement and drug delivery. The surface groups played an important role in dendrimer-mediated solubility enhancement.

Ex vivo permeability experiments in excised rat intestinal tissue and in vitro solubility measurements in aspirated human intestinal fluids support age-dependent oral drug absorption

The possible influence of advanced age on intestinal drug absorption was investigated by determining the effects of aging on (i) solubility of model drugs in human intestinal fluids (HIF) obtained from two age groups (18–25 years; 62–72 years); and (ii) transepithelial permeation of model drugs across intestinal tissue excised from young, adult and old rats. Average equilibrium solubility values for 10 poorly soluble compounds in HIF aspirated from both age groups showed high interindividual variability, but did not reveal significant differences. Characterization of the HIF from both age groups demonstrated comparable pH profiles, while concentrations of individual bile salts showed pronounced variability between individuals, however without statistical differences between age groups. Transepithelial permeation of the transcellular probe metoprolol was significantly increased in old rats (38 weeks) compared to the younger age groups, while the modulatory role of P-glycoprotein in transepithelial talinolol transport was observed in adult and old rats but not in young rats. In conclusion, age-dependent permeability of intestinal tissue (rather than age-dependent luminal drug solubility) may contribute to altered intestinal drug absorption in older patients compared to young adults.

A new type of double-layered osmotic pump controlled release tablets of bezafibrate with poor water solubility and large dosage

A new type double-layered osmotic pump (DOP) system was developed for the delivery of water insoluble drug bezafibrate with daily dose of 400 mg, polymer was used as drug carrier and alkaline substance was added to the core as solubilizer. This novel DOP was designed as a combination of various osmotic pumps, such as push-pull osmotic pump, elementary osmotic pump and monolithic polymer osmotic pump. Two layers of the osmotic pump system were both drug-containing, the first layer of the DOP was designed using elementary osmotic pump theory which involved 20 mg sodium carbonate to enhance the solubility of model drug, the second layer was designed using monolithic polymer osmotic pump theory by adding 50 mg polyoxyethylene oxide as suspending and swelling agent, and a double layer osmotic pump was formed by the combination of the two layers which could operate as a push-pull osmotic pump. Orifices with the same diameter at 0.8 mm were drilled on both sides of membrane surfaces and the release profile of drug presented zero-order in 12 h. The results showed that factors that had considerable influence on in vitro drug release behavior were: the proportion of bezafibrate in two layers, the amount of polyoxyethylene oxide in core tablets, the percentage of polyethylene glycol in coating materials, the coating level and the orifice.

Impact of the Amount of Excess Solids on Apparent Solubility

The impact of excess solids on the apparent solubility is examined. The apparent solubility of some model drugs was measured in various buffered solutions, with various amounts of excess solid. To help understand the dependence of the solubility on the amount of solid, we evaluated the dissolution and crystallization rates of indomethacin (IDM), one of the model drugs, at near-equilibrium conditions. In the case of IDM, the apparent solubility decreased with an increase in the solid amount at pH 5 and 6. On the other hand, it increased with an increase in the solid amount at pH 6.5 and 7. The crystallization and dissolution rates of IDM decreased and increased, respectively, with an increase in pH values, and became equal at between pH 6 and 7. Therefore, the apparent solubility was most likely to be affected by the balance between the crystallization and dissolution rates. The apparent solubility of other model drugs showed the same trend, although the dependency on the solid amount was not as significant as in the case of IDM. The apparent solubility was affected by the amount of solid for all the model drugs investigated. This was most likely to be caused by a competition between the crystallization and dissolution rates.

Co-effect of aqueous solubility of drugs and glycolide monomer on in vitro release rates from poly(D,L-lactide- co-glycolide) discs and polymer degradation

The objective of this study was to investigate the effect of aqueous solubility of model drugs and glycolide monomer (GM) from poly(D,L -lactide-co-glycolide) (PLGA) discs on in vitro release rates and polymer degradation. 5-Fluorouracil (5-FU), a water-soluble compound, and dexamethasone in a water-insoluble base form were selected as model drugs. Glycolide monomer, that has moderate solubility in water, was a non-toxic and biodegradable additive as a derivative material of hydrolysis of PLGA in order to obtain desirable drugs release rates. PLGA discs with or without GM were formulated by means of compression molding method. The prepared polymeric discs were incubated at 37°C in phosphate-buffered saline (PBS, pH 7.4) and characterized at scheduled time points for water uptake, mass loss, diameter and morphology change, molecular weight and composition change using scanning electron microscopy (SEM), gel-permeation chromatography (GPC), and 1H-NMR, respectively. The supernatants were taken out of the sample vials and were analyzed for drug release. The 5-FU release was found to be increasing in proportion to the drug loading amount with an initial burst for 5 days, while dexamethasone release showed inverse relationship with the increasing drug loading amount. However, the release behaviors of 5-FU and dexamethasone polymeric discs containing GM showed faster release rates than control discs (without GM) and did not show lag periods during the in vitro release test due to adding GM, which acted as a channeling agent that has moderate solubility in water. Polymer degradation was found to be affected by aqueous solubility of drugs and GM. In conclusion, we observed that drugs release rates were influenced by their aqueous solubility and loading amount and also GM plays a major role in controlling drug release rates regardless of solubility of drugs. This system appears to be promising for controlled drug delivery aimed at local therapy.

Biodegradable Self-Assembling PEG-Copolymer as Vehicle for Poorly Water-Soluble Drugs

To develop self-assembling systems increasing the solubility of poorly water-soluble drugs. Low molecular weight liquid biodegradable copolymers were synthesized by ring-opening polymerization using caprolactone (CAP) and trimethylenecarbonate (TMC) as monomers. Various initiators were evaluated. The emulsifying and self-assembling properties were investigated by a water titration method. The self-assembling systems were characterized for size, shape, isotropic behavior, cloud point, surface charge, and critical micellar concentration in order to optimize the polymer synthesis. Finally, the improvement of solubility of model drugs was assessed. Only diblock monomethyl ether PEG-CAP/TMC copolymers synthesized with monomethyl ether polyethyleneglycol 550 to 2000 as initiator have shown self-assembling properties: upon dilution, these copolymers formed an isotropically clear solution with droplet sizes in the range of 20 to 100 nm. The hypothesis that these diblock polymers form micelles was confirmed by their low critical micellar concentration (10(-5) g/ml). The copolymers initated with mmePEG750 had a higher cloud point and better colloidal stability than those initiated with mmePEG 550. The solubility of the poorly water-soluble drugs was increased by 1 to 2 orders of magnitude. Good reproducibility was observed from batch to batch. The polyester diblock copolymer mmePEG750-CAP/TMC forms spontaneously stable micelles in aqueous medium and increases the solubility of lipophilic drugs. They are very promising vehicles for the oral delivery of poorly water-soluble drugs.

Study of isopropyl myristate microemulsion systems containing cyclodextrins to improve the solubility of 2 model hydrophobic drugs.

The objectives of this project were to evaluate the effect of alkanols and cyclodextrins on the phase behavior of an isopropyl myristate microemulsion system and to examine the solubility of model drugs. Triangular phase diagrams were developed for the microemulsion systems using the water titration method, and the solubility values of progesterone and indomethacin were determined using a conventional shake-flask method. The water assimilation capacities were determined to evaluate the effective microemulsion formation in different systems. The alkanols showed higher microemulsion formation rates at higher concentrations. A correlation between the carbon numbers of the alkanol and water assimilation capacity in the microemulsions studied was observed; isobutanol and isopentanol produced the best results. The addition of cyclodextrins showed no effect or had a negative effect on the microemulsion formation based on the type of cyclodextrin used. Isopropyl myristate-based microemulsion systems alone could increase the solubility values of progesterone and indomethacin up to 3300-fold and 500-fold, respectively, compared to those in water. However, the addition of cyclodextrins to the microemulsion systems did not show a synergistic effect in increasing the solubility values of the model drugs. In conclusion, microemulsion systems improve the solubility of progesterone and indomethacin. But the two types of cyclodextrins studied affected isopropyl myristate-based microemulsion systems negatively and did not improve the solubilization of 2 model drugs.

Formulation and characterization of amphotericin B–polyethylenimine–dextran sulfate nanoparticles

A new aqueous nanoparticle system has been developed using complex coacervation employing the oppositely charged polymers polyethylenimine (PEI) and dextran sulfate (DS), with zinc sulfate as a stabilizing agent. Amphotericin B (AmB) was loaded into the nanoparticles as a model drug. The nanoparticles contained PEI and DS in the weight ratio of ∼1:2. They possessed a zeta potential of approximately +30 mV and demonstrated a narrow size distribution in the range 100–600 nm with a polydispersity index of 0.2. Electron microscopy revealed spherical nanocapsules with a smooth surface. Very favorable drug entrapment and recovery efficiencies of up to 85% were routinely observed. Processing parameters, such as the pH of the PEI solutions, ratio of the two polymers, as well as the concentrations of DS and zinc sulfate, all played a significant role in controlling particle size. Dissolution studies demonstrated a fast release that is dependent on the model drug solubility. The AmB‐loaded nanoparticles displayed no toxicity in tissue culture in contrast to free drug and were almost as efficacious as free drug in killing Candida albicans. Advantages of this simple technique are (1) ease of manufacturing and mild preparation conditions, (2) employment of completely aqueous processing conditions, (3) use of biocompatible polymers that can be prepared aseptically, (4) ability to control their size, and (5) a high level of drug entrapment. © 2001 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:902–914, 2001

A novel in vitro release method for submicron sized dispersed systems.

Sink conditions are often violated when using conventional release methods for dispersed systems. A novel reverse dialysis bag method was designed to overcome this problem. Model drug transport rates from submicron emulsions obtained using the conventional diffusion cell method and this novel method were compared. In the side-by-side diffusion cell method, emulsions were placed in the donor chamber and surfactant/buffer solutions in the receiver chamber. In the novel dialysis bag method, emulsions were diluted infinitely in the donor phase and surfactant/buffer solutions were placed in the receiver phase (dialysis bags). Slow release rates and linear release profiles were obtained using the side-by-side diffusion cell method apparently due to limited model drug solubility in the donor chamber resulting in violation of sink conditions. Biphasic release profiles were obtained using the dialysis bag method apparently due to an initial rapid release of free and micellar solubilized model drug from the donor to the receiver chambers followed by slow release from the oil droplets. Using both release methods, an initial increase and latter decrease in release rates were observed with increase in surfactant concentration. The initial increase was considered to be due to a decrease in the model drug oil-in-water partition coefficients and the subsequent decrease in release rates was due to micellar shape change (spheres to rods) causing a decrease in diffusion rates. Sink conditions were violated using the side-by-side diffusion cell method but were maintained in the dialysis bag method since emulsions were diluted infinitely in the donor phase.