Nonionic Hydrophilic Polymer Research Articles

Design and Optimization of a Polyethylene Oxide-Based Matrix Tablet of Metoprolol Succinate Using Design Expert Software

Hypertension is a common lifestyle disorder, the prevalence of which advances with age. In the case of antihypertensive therapy, patient compliance is hampered, especially in geriatric patients, if the dose is b.i.d or more, as it is difficult for the patient to remember and take medicine at a scheduled time. The present study involves the fabrication of a sustained-release matrixdesigned tablet using a combination of polyethylene oxide (PEO) polymers and metoprolol succinate as the model drug. The tablet is optimized and evaluated for its in-vitro release using the Design expert software. Polyethylene oxide is a non-ionic hydrophilic polymer which is directly compressible. Polyox WSR 301 and 303 grades have been used in the study to get the desired sustained release of 12 h. The formulations were analysed for various pre-compression and post-compression characteristics. The polymers Polyox WSR 301 and 303 influence drug release are measured using a 32 factorial design where the concentration of drug released at various time points has been analysed statistically as a response. Response surface plots demonstrate and depict the effect of the variables, thus aiding in optimization. All the formulated batches exhibited acceptable pre and post-compression characteristics. The optimized formulation M05 showed a sustained drug release up to a 12 h period. Thus polyethylene oxide can be used as an excellent sustained-release matrix polymer due to its ability to gel and prolong drug release from a matrix. Due to their molecular weight, a combination of two grades of polyethylene oxide helps reinforce the drug release.

Antifouling polymers for nanomedicine and surfaces: recent advances.

Antifouling polymers are materials that can resist nonspecific interactions with cells, proteins, and other biomolecules. Typically, they are hydrophilic polymers with polar or charged moieties that are capable of strong nonbonding interactions with water molecules. This propensity to bind water generates a surface hydration layer that reduces nonspecific interactions with other molecules and is paramount to the antifouling behavior. This property is especially useful for nanoscale applications such as nanomedicine and surface modifications at the molecular level. In nanomedicine, antifouling polymers such as poly(ethylene glycol) and its alternatives play a key role in shielding drug molecules and therapeutic proteins/genes from the immune system within nanoassemblies, thereby enabling effective delivery to target tissues. For coatings, antifouling polymers help to prevent adhesion of cells and molecules to surfaces and are thus valued in marine and biomedical device applications. In this Review, we survey recent advances in antifouling polymers in the context of nanomedicine and coatings, while shining the spotlight on the major polymer classes such as PEG, polyzwitterions, poly(oxazoline)s, and other nonionic hydrophilic polymers.

Author Correction: Photoinduced self-initiated graft polymerization of methacrylate monomers on poly(ether ether ketone) substrates and surface parameters for controlling cell adhesion

One of the super engineering plastics, poly(ether ether ketone) (PEEK), was functionalized by photoinduced self-initiated graft polymerization of various methacrylate monomers. Anionic, cationic, zwitterionic, nonionic hydrophilic, and nonionic hydrophobic polymer layers were formed onto PEEK substrates. Physical and chemical surface characterizations of the resultant polymer-grafted PEEK substrates were performed through measurements of their surface free energies and ζ potentials. The values of these parameters varied in the ranges of 39–71 mJ/m2 and −69 to 46 mV, respectively. These parameters reflected the chemical structures of the grafted polymers. To understand the effects of these surface parameters on cell adhesion behavior at the substrate surface, the amount of fibronectin adsorbed on the plasma-contacting surface and the density of fibroblast cells adhered to the surface were determined. The adherent cell density showed a good linear correlation with the amount of fibronectin adsorbed on the plasma-contacting surface. The polymer surface with zero ζ potential showed a lower adsorbed fibronectin density. Both anionic and cationic polymer layers had increased cell adhesion compared with that on the original PEEK substrate, whereas the zwitterionic polymer layers significantly prevented cell adhesion. In conclusion, grafting zwitterionic polymers onto a PEEK substrate is anticipated to be useful in the development of a biomedical PEEK substrate. To obtain functionalization of super-engineering plastic, poly(ether ether ketone) (PEEK) substrate, photoinduced self-initiated graft polymerization of several kinds of functional methacrylate was carried out. Graft polymerization proceeded well, and 50–250 nm in thickness graft polymer layers were generated on the PEEK substrate. Surface characteristics such as surface free energy and surface ζ potential on the polymer-grafted PEEK substrate were corresponded to the chemical structure of the graft polymers. Cell attachment on the polymer-grafted PEEK substrate was examined. The surface ζ potentials of the polymer-grafted PEEK substrates governed the cell adhesion density.

Anaphylaxis due to macrogol in a laxative solution with a positive basophil activation test

Polyethylene glycol (otherwise known as macrogol or PEG) belongs to a family of synthetic nonionic hydrophilic polymers achieved as condensation products of glycols with ethylene oxide. Different types of macrogol exist, each with a specific molecular weight (from 200 to 20,000 g/mol) and length, which gives them specific pharmacological qualities (eg, viscosity, density). As a consequence, PEG has wide applications as an excipient, solvent, dispersing, and thickening agent in the food, cosmetic, medical, and pharmaceutical industries.

Role of Charge of Micellar Worms in Modulating Structure and Rheological Properties of Their Mixtures with Nonionic Polymer

The paper describes phase behavior, microstructure, and rheological properties of the mixtures of surfactant micelles of varying negative charge with nonionic hydrophilic polymer poly(vinyl alcohol) (PVA) weakly interacting with the micelles. To reduce the charge of micelles, a cationic surfactant n-octyltrimethylammonium bromide was gradually added to the anionic surfactant potassium oleate. No appreciable interactions between the micelles and polymer were revealed by NMR spectroscopy. At the same time, the system shows a broad range of compatibility, which may be due to surfactant counterions preventing the demixing. The higher the concentration of added polymer, the higher the charge density of micelles necessary to prevent macrophase separation. However, SANS data demonstrate that upon the addition of polymer the intermicellar distances decrease, which suggests that the micelles are expelled from some area filled by PVA macromolecules, indicating a local demixing. A decrease of micellar charge density...

Viscoelastic Synergy and Microstructure Formation in Aqueous Mixtures of Nonionic Hydrophilic Polymer and Charged Wormlike Surfactant Micelles

We studied the effect of neutral polymer poly(vinyl alcohol) on the rheological properties and microstructure of highly charged mixed wormlike micelles of anionic and cationic surfactants, potassium oleate and n-octyltrimethylammonium bromide, without adding salt. It was shown that the polymer induces a hundredfold increase of viscosity and of longest relaxation time and the appearance of well-defined plateau modulus, which was assigned to interlacing of polymer and micellar chains. When the amount of added polymer exceeds 2 wt %, the rheological characteristics (the viscosity, the longest relaxation time, and the plateau modulus) level off because of microphase separation appearing as a result of the interplay of the segregation on the microscopic scale triggered by the energetic repulsion between polymer and surfactant components, on the one hand, and the translational entropy of counterions preventing the macroscopic phase separation, on the other hand. The formation of surfactant-rich and polymer-rich...

Chemical hybridizations of polyurethanes with fillers

materials whose properties are closely tailored by the structure-property relationship. This leads to a broad property spectrum including foam, coating, adhesive, sealant, and elastomer with an annual production over 12 million tons. Recently, functionalization or hybridization with reinforcing materials opened up even a broad spectrum with value added products in market. Among others, waterborne type (WPU) was the first commercialized in late 1980s to reduce the solvent emission. This was done by introducing ionic groups viz. carboxylic or sulfonate groups, and/or nonionic hydrophilic polymer segments such as polyethylene oxide into the PU. When the isocyanate termini of the PU prepolymer (hereafter called IPU) are exposed to water or moisture, unstable carbamic acid is formed. This gives off carbon dioxide to form amine ends which react with the isocyanate termini to make chain extension or cross-linking. Water curable PUs are applied for molding the orthopedic socket and gypsum. IPUs are the key for chemical hybridization. They are directly reacted with the OH groups of many inorganic and organic fillers such as silica, graphene, clay, starch, gelatin, cellulose etc to form chemical hybrids. Among them, hybrids with sustainable raw materials (starch, gelatin, cellulose etc) become bio degradable. Moreover, fillers carrying multiple OH groups provide the hybrids with multifunctional cross-links which give much higher strength and modulus, especially in rubbery state as compared with the conventional cross-links. The enhanced rubbery modulus augmented the elastic recoil with minimum cyclic hysteresis. A second way of modification is done by capping the IPU with hydroxyl acrylates, typically hydroxyethylacrylate, which is generally followed by UV curing to render cross-linking or hybrids with inorganic fillers such as fumed silica. Prior to the incorporation, acrylic functionality such as vinyltrimethoxysilane (VTMS) or allyl isocyanate (DOI: 10.1002/pola. 24473) is introduced into the fillers. Silica acted as multifunctional cross-link as well as reinforcing filler to provide over 99% shape fixity and shape recovery with only 1% (DOI: 10.1039/b922775j). The UV curing of PU or WPU synergistically combined the advantages of WPU (tack-free) and UV cure (fast), which is a great advantage for coating applications. The IPU can directly react with OH groups of fillers to form hybrids (DOI: 10.1039/c1jm10722d). Or, the IPU can be end capped with glycidol to introduce epoxy groups on the termini, which are subsequently reacted with 3-aminopropyltriethoxysilane (APTES) to form APTES extended PU. The ethoxy groups react with OH groups of fillers via sol-gel type reactions to form chemical hybrids (DOI: 10.1039/ b816691a). In both cases, fillers act as multifunctional cross-links and reinforcement. Novel PUs are yet to come with multiple hybridization and functionalization along with non-isocyanate route.

In vitro hemocompatibility and cytotoxicity study of poly(2‐methyl‐2‐oxazoline) for biomedical applications

AbstractSince poly(2‐methyl‐2‐oxazolines) (PMeOx) attract high attention for the potential use in drug delivery, cytotoxicity, and hemocompatibility of a set of PMeOxs with molar masses in the range from 2 to 20 kDa are systematically investigated under standardized conditions in terms of molar mass, concentration and time dependency. PMeOx polymers are well tolerated in red blood cell aggregation and hemolysis assays without any damaging effects even at high concentrations up to 80 mg/mL. Only in long term cytotoxicity tests PMeOx polymers moderately influence cell viability in a time, concentration, and molar mass dependent manner. Referring to these results it can be concluded that PEtOx could be promising nonionic hydrophilic polymers for many biomedical applications without any cyto‐ and hemotoxic effects at typically used therapeutic doses. © 2013 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2013

Formation of Dynamic Duolayer Systems at the Air/Water Interface by using Non-ionic Hydrophilic Polymers

The inclusion of a water-soluble polymer, poly(vinyl pyrrolidone) (PVP), into a surface active film composition before application to the water surface leads to the formation of a dynamic duolayer; a novel surface film system. This duolayer shows improved surface viscosity over the monolayer compound alone, while the addition of polymer maintains other film properties such as evaporation control and equilibrium spreading pressure. Brewster Angle Microscopy shows that the duolayer film undergoes a different formation mechanism upon film compression, and the resultant surface pressure/area isotherm is different at lower surface pressures indicating the PVP is present on the water surface at these pressures and squeezed out to the water subphase at higher pressures. The addition of water-soluble polymers to form a dynamic duolayer provides a unique way to produce defect-free and tightly packed films while polymer is associated with the film. This finding provides new knowledge for the design of surface films with improved properties with potential applications in many areas.

Insights into the Role of Polymer-Surfactant Complexes in Drug Solubilisation/Stabilisation During Drug Release from Solid Dispersions

To evaluate the role of polymer-surfactant interactions in drug solubilisation/stabilisation during the dissolution of spray-dried solid dispersions and their potential impact on in vivo drug solubilisation and absorption. Dissolution/precipitation tests were performed on spray-dried HPMC-Etravirine solid dispersions to demonstrate the impact of different surfactants on the in vitro performance of the solid dispersions. Interactions between HPMC and bio-relevant and model anionic surfactants (bile salts and SDS respectively) were further characterised using surface tension measurements, fluorescence spectroscopy, DLS and SANS. Fast and complete dissolution was observed in media containing anionic surfactants with no drug recrystallisation within 4 h. The CMCs of bile salts and SDS were dramatically reduced to lower CACs in the presence of HPMC and Etravirine. The maximum increases of the apparent solubility of Etravirine were with the presence of HPMC and SDS/bile salts. The SANS and DLS results indicated the formation of HPMC-SDS/bile salts complexes which encapsulated/solubilised the drug. This study has demonstrated the impact HPMC-anionic surfactant interactions have during the dissolution of non-ionic hydrophilic polymer based solid dispersions and has highlighted the potential relevance of this to a fuller understanding of drug solubilisation/stabilisation in vivo.

Functional polymer brushes via surface-initiated atom transfer radical graft polymerization for combating marine biofouling

Dense and uniform polymer brush coatings were developed to combat marine biofouling. Nonionic hydrophilic, nonionic hydrophobic, cationic, anionic and zwitterionic polymer brush coatings were synthesized via surface-initiated atom transfer radical polymerization (SI-ATRP) of 2-hydroxyethyl methacrylate, 2,3,4,5,6-pentafluorostyrene, 2-(methacryloyloxy)ethyl trimethylammonium chloride, 4-styrenesulfonic acid sodium and N,N′-dimethyl-(methylmethacryloyl ethyl) ammonium propanesulfonate, respectively. The functionalized surfaces had different efficacies in preventing adsorption of bovine serum albumin (BSA), adhesion of the Gram-negative bacterium Pseudomonas sp. NCIMB 2021 and the Gram-positive Staphylococcus aureus, and settlement of cyprids of the barnacle Amphibalanus amphitrite (=Balanus amphitrite). The nonionic hydrophilic, anionic and zwitterionic polymer brushes resisted BSA adsorption during a 2 h exposure period. The nonionic hydrophilic, cationic and zwitterionic brushes exhibited resistance to bacterial fouling (24 h exposure) and cyprid settlement (24 and 48 h incubation). The hydrophobic brushes moderately reduced protein adsorption, and bacteria and cyprid settlement. The anionic brushes were least effective in preventing attachment of bacteria and barnacle cyprids. Thus, the best approach to combat biofouling involves a combination of nonionic hydrophilic and zwitterionic polymer brush coatings on material surfaces.

Klucel™ EF and ELF polymers for immediate-release oral dosage forms prepared by melt extrusion technology

The objective of this research work was to evaluate Klucel™ hydroxypropylcellulose (HPC) EF and ELF polymers, for solubility enhancement as well as to address some of the disadvantages associated with solid dispersions. Ketoprofen (KPR), a Biopharmaceutics Classification System class II drug with poor solubility, was utilized as a model compound. Preliminary thermal studies were performed to confirm formation of a solid solution/dispersion of KPR in HPC matrix and also to establish processing conditions for hot-melt extrusion. Extrudates pelletized and filled into capsules exhibited a carrier-dependent release with ELF polymer exhibiting a faster release. Tablets compressed from milled extrudates exhibited rapid release owing to the increased surface area of the milled extrudate. Addition of mannitol (MNT) further enhanced the release by forming micro-pores and increasing the porosity of the extrudates. An optimized tablet formulation constituting KPR, MNT, and ELF in a 1:1:1 ratio exhibited 90% release in 15min similar to a commercial capsule formulation. HPC polymers are non-ionic hydrophilic polymers that undergo polymer-chain-length-dependent solubilization and can be used to enhance solubility or dissolution rate of poorly soluble drugs. Dissolution/release rate could be tailored for rapid-release applications by selecting a suitable HPC polymer and altering the final dosage form. The release obtained from pellets was carrier-dependent and not drug-dependent, and hence, such a system can be effectively utilized to address solubility or precipitation issues with poorly soluble drugs in the gastrointestinal environment.

Preparation of Novel Emulsion Gel Adsorbents and Their Adsorption Properties for Heavy-Metal Ions

Novel emulsion gel adsorbents were developed for metal adsorption. Poly[poly(ethylene glycol) methyl ether acrylate] [poly(PEGMEA)] was used as a nonionic hydrophilic polymer, and 2-ethylhexylphosphoric acid mono-2-ethylhexyl ether (EHPNA) was used as an organophosphorus extractant for rare metal ions. Poly(PEGMEA) hydrogel containing randomly distributed oil microdroplets of EHPNA were prepared by the emulsion–gelation method using oil-in-water emulsions under various monomer concentrations, oil volume fractions, and surfactant concentrations. The emulsion gel successfully adsorbed In(III) ions used as a representative metal. Mutual separation of In(III) and Zn(II) ions and repeated adsorption were successful because of the pH dependence of the metal–extractant complexation. The emulsion gel has a higher degree of compressive deformation and abrasion resistance than a conventional (nonemulsion) hydrogel and shows potential for use in practical separations.

Incorporation of Carbon Nanotubes into a Lyotropic Liquid Crystal by Phase Separation in the Presence of a Hydrophilic Polymer

Single-walled carbon nanotubes (SWNTs) were incorporated into a lyotropic liquid crystal (LLC) matrix formed by n-dodecyl octaoxyethene monoether (C(12)E(6)) at room temperature through spontaneous phase separation induced by nonionic hydrophilic polymer poly(ethylene glycol) (PEG). The quality of SWNTs/LLC composite was evaluated by polarized microscopy observations and small-angle X-ray scattering (SAXS) measurements. The results obtained clearly indicated that SWNTs have been successfully incorporated into the LLC matrix up to a considerable high content without destroying the LLC matrix, although interesting changes of the LLC matrix were also induced by SWNTs incorporation. By varying the ratio of PEG to C(12)E(6), the type of LLC matrix can be controlled from hexagonal phase to lamellar phase. Temperature was found to have a significant influence on the quality of SWNTs/LLC composite, and tube aggregation can be induced at higher temperature. When SWNTs were changed to multiwalled carbon nanotubes (MWNTs), they became difficult to be incorporated into LLC matrix because of an increase in the average tube diameter.

Functional characterisation of Fab′-fragments self-assembled onto hydrophilic gold surfaces

Antibody Fab′-fragments have been immobilised on hydrophilic gold by direct self-assembly, and embedded in a matrix of non-ionic hydrophilic polymers, tris(hydroxymethyl)methylacrylamide, carrying lipoate terminal linking groups. Different polymers were synthesised, and co-adsorbed or post-adsorbed between the antibody fragments in order to optimise the antigen binding. Various factors were investigated that influence the activity of the immobilised Fab′-fragments for binding of the antigen, human IgG. The Fab′-fragments were immobilised in dense layers close to monolayer coverage, and the stoichiometric efficiency of immobilisation was up to 30%, with the human IgG also approaching monolayer coverage. The cleaning of the gold surface was a crucial factor in preservation of activity. Besides the usual treatment in hot ammonia/peroxide solution, hot DMSO appeared to be highly effective as a cleaning agent.

A comparative evaluation of molecular recognition by monolayers composed of synthetic receptors or oriented antibodies

Recombinant anti-morphine Fab′ fragments have been immobilised on gold by covalent attachment through the free thiol groups of the fragment. The antibody fragments were intercalated with a non-ionic hydrophilic polymer in order to suppress non-specific binding of interfering substances. The antibodies are oriented on the surface due to the thiol groups of the antibody and the layer shows a high response to antigen. Non-specific binding of bovine serum albumin is moreover very low because of the repellent polymer. Synthetic receptors composed of an imprinted self-assembled monolayer made from lipoates and the template, morphine, exhibit the same binding response to the antigen, morphine as the site-specific oriented antibody monolayer. A similar binding curve could be obtained as that for binding of morphine to an antibody Fab′ fragment/polymer layer – indicating that synthetic receptors produced are comparable to those of antibody layers. Concentrations down to 0.1 ng/ml have been measured with surface plasmon resonance.

Covalent modified hydrophilic polymer brushes onto poly(dimethylsiloxane) microchannel surface for electrophoresis separation of amino acids

A new environmentally friendly method is developed for preventing nonspecific biomolecules from adsorption on poly(dimethylsiloxane) (PDMS) surface via in situ covalent modification. o-[( N-Succinimdyl)succiny]- o′-methyl-poly(ethylene glycol) (NSS-mPEG) was covalently grafted onto PDMS microchannel surface that was pretreated by air–plasma and silanized with 3-aminopropyl-triethoxysilanes (APTES). The modification processes were carried out in aqueous solution without any organic solvent. The mPEG side chains displayed extended structure and created a nonionic hydrophilic polymer brushes layer on PDMS surface, which can effectively prevent the adsorption of biomolecules. The developed method had improved reproducibility of separation and stability of electroosmotic flow (EOF), enhanced hydrophilicity of surface and peak resolution, and decreased adsorption of biomolecules. EOF in the modified microchannel was strongly suppressed, compared with those in the native and silanized PDMS microchips. Seven amino acids have been efficiently separated and successfully detected on the coated PDMS microchip coupled with end-channel amperometric detection. Relative standard deviations (RSDs) of their migration time for run-to-run, day-to-day and chip-to-chip, were all below 2.3%. Moreover, the covalent-modified PDMS channels displayed long-term stability for 4 weeks. This novel coating strategy showed promising application in biomolecules separation.

Self-assembly of antibody fragments and polymers onto gold for immunosensing

In order to obtain a site-specific orientation of antibodies for immunosensing and prevent non-specific binding (NSB) antibody Fab′-fragments have been immobilized directly onto gold and the remaining free space in between the antibodies have been coated by a non-ionic hydrophilic polymer of N-[tris(hydroxy-methyl)methyl]acrylamide. The polymer possesses low NSB and can be covalently attached onto the gold surface by disulfide anchors. The antibody fragments were to be embedded in the protein repellent host matrix in such a way that only the antigen binding part of the antibody sticks out from the monolayer surface. Thus, NSB binding to the host matrix and to the antibody fragments could be reduced and a high antigen binding capacity could be obtained. Surface plasmon resonance, SPR has been used to compare the attachment of antibody F(ab) 2 and Fab′-fragments of anti-human IgG onto gold. Antibody Fab′-fragments directly coupled onto gold give a three-fold response to human IgG (hIgG) to that of F(ab) 2-fragments. The Fab′-fragment layer could be regenerated with a glycine–HCl solution. The F(ab) 2-fragment layer, on the other hand, could not be regenerated. This indicates a difference in immobilisation of the fragments. The F(ab) 2-fragments were adsorbed on the surface and thus randomly oriented. The much higher binding capacity and the ability to regenerate the Fab′-fragment layer indicates that the Fab′-fragments were site-directly immobilised on the gold surface. When antibody Fab′-fragments were allowed to interact with the surface and the remaining free space in between the antibodies were filled with the protein repellent polymer the NSB was considerably reduced.

Interactions of glucose and polyacrylamide in solutions and gels

AbstractThe swelling of polyacrylamide (PAAm) gels increased with rising glucose concentrations, and so did the osmotic pressure of the soluble polymer and its intrinsic viscosity. A Flory–Huggins‐based model for the osmotic pressure of a nonionic hydrophilic polymer in a ternary solution consisting of a main solvent, a polymer, and a nondissociating low‐molecular‐weight cosolute was developed and examined. The model‐calculated values were in reasonably good agreement with experimental results for the water–PAAm–glucose system studied when PAAm–water and glucose–water interaction coefficients from the binary systems were used, and only the PAAm–glucose interaction coefficient was adjusted. Its negative value suggested a favorable interaction of glucose and PAAm, supporting the notion of glucose being a good cosolvent for PAAm. Isothermal titration microcalorimetry results showed no evidence for the binding of glucose to PAAm, but an exothermic interaction was indicated between glucose and PAAm. Microcalorimetrically determined enthalpic contributions to the Flory–Huggins interaction coefficients showed enthalpically favorable binary interactions, particularly the enthalpic component of the PAAm–glucose interaction coefficient (χH23), which was slightly negative. The enthalpically favorable interaction between glucose and PAAm may explain the increased osmotic pressure of PAAm in glucose solutions. © 2003 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 41: 3053–3063, 2003

이트라코나졸의 경구용 액제 처방화

The oral bioavailability of itraconazole is variable and low in fasting state. This is mainly due to the low solubility of this drug. Bioavailability can be improved by changing the formulation and it is general that the liquid preparations show greater bioavailability than the solid dosage forms such as tablets and capsules do. Benzyl alcohol-water binary mixture showed the excellent solubilizing capacity for itraconazole but the release of the drug from the preparation needs to be enhanced. In this study, various nonionic surfactants and hydrophilic polymers, poloxamers, were screened to investigate their effects on the release of itraconazole from the liquid preparations. Poloxamer 407 showed the most enhancing effect on the drug release and the release rate was proportional to the amount of poloxamer 407 added. A liquid preparation of itraconazole, consisting of benzyl alcohol/water/poloxamer 407 ternary solvent system, released more than 80% of the total drug amount at 5 min and showed the possibility of a new formulation development.