Porous PLGA microparticles prepared with nanosized/micronized sugar particles as porogens.

The objective of this study was to explore the use of nanosized/micronized sugar particles as porogens for preparing porous poly(lactide-co-glycolide) (PLGA) microparticles by a solid-in-oil-in-water (S/O/W) solvent evaporation method. Porous PLGA microparticles containing dexamethasone were prepared with different nanosized/micronized sugars (sucrose, trehalose and lactose), types of PLGA, and osmogens (NaCl or sucrose) in the external water phase. The microparticles were characterized for morphology, thermal properties, particle size, surface area, encapsulation efficiency and drug release/swelling during release. The addition of nanosized/micronized sugar particles resulted in porous PLGA microparticles with high encapsulation efficiencies. The porosity of the microparticles was caused both by the influx of water into the polymer droplets and the encapsulation and subsequent dissolution of sugar particles during the manufacturing process. The porosity (pore size) of the microparticles and, as a result, the drug release pattern could be well controlled by the particle size and weight fraction of the sugar particles. Because of a larger inner surface area, nanosized sugar particles were more efficient porogen than micronized sugar particles to obtain porous PLGA microparticles with flexible release patterns.

Direct drug milling in organic PLGA solution facilitates the encapsulation of nanosized drug into PLGA microparticles.

The objective of this study was to prepare poly(lactide-co-glycolide) (PLGA) microparticles loaded with nanosized drug by combining non-aqueous wet bead milling and microencapsulation. 200-300 nm dexamethasone, hydrocortisone and dexamethasone sodium phosphate nanosuspensions were successfully prepared by wet bead milling the drug in dichloromethane using PLGA as a stabilizer. PLGA microparticles loaded with nanosized drugs were then prepared by a solid-in-oil-in-water (S/O/W) solvent evaporation method or solid-in-oil-in-oil (S/O/O) organic phase separation method. The microparticles were characterized by laser diffraction (LD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) and in vitro drug release. The nanosized drugs were homogeneously distributed within the microparticle matrix and remained crystalline, however, with a decrease in crystallinity. High drug encapsulation efficiencies >80 % were achieved at theoretical drug loadings between 5 and 30 %. Drug release profiles could be controlled by varying PLGA grades/blends, microparticle size and drug loadings. Quasi-linear release profiles without the PLGA-typical slow release phase were achieved with PLGA encapsulated nanosized drug.

A comparative study of PLGA microparticle properties loaded with micronized, nanosized or dissolved drug.

The objective of this study was to compare properties of poly(lactide-co-glycolide) (PLGA) microparticles loaded with dexamethasone or hydrocortisone in the micronized, nanosized or dissolved state. Dexamethasone and hydrocortisone were nanosized by wet bead milling. The microparticles were prepared by a solvent extraction/evaporation method and were characterized by particle size, encapsulation efficiency, drug solid-state, morphology, in vitro release and dynamic microparticle diameter changes during release. The micronized and nanosized drugs were still in crystalline form after encapsulation into PLGA microparticles with encapsulation efficiencies greater than 85 %. Encapsulating dissolved drugs resulted in lower encapsulation efficiencies (32 to 63 %) and the dissolved drug recrystallized within the PLGA matrix at a higher actual drug loading of 30 %. The order in drug release depended on the physical state of the encapsulated drug and was in the order of dissolved > nanosized > micronized drug. Interestingly, quasi-linear release profiles were obtained with 10 % nanosized dexamethasone in PLGA 502H and 503H microparticles. In conclusion, encapsulating dispersed and, in particular, nanosized drug into PLGA microparticles is a promising tool to increase the encapsulation efficiency, to maintain a stable drug solid-state and to achieve a more continuous release profile.

Polymer type effect on PLGA-based microparticles preparation by solvent evaporation method with single emulsion system using focussed beam reflectance measurement.

AIM: This study aimed to investigate the effect of polymer type on solidification rate of PLGA polymeric microparticles and particle size/distribution of the emulsion droplets/hardened PLGA polymeric microparticles during solvent evaporation process using FBRM (Focussed Beam Reflectance Measurement). METHODS: PLGA polymeric microparticles were prepared by an O/W solvent evaporation method using various PLGA polymers, including PLGA Resomer® RG503H, RG502H and RG752H. The particle size mean, chord length distribution (CLD), and chord count of the emulsion droplets/hardened microparticles were monitored by FBRM. The morphology of polymeric microparticles were characterised by optical microscopy and scanning electron microscopy (SEM). RESULTS: The transformation of the emulsion droplets into solid microparticles occurred within the first 30 (± 1.04), 34 (± 1.15) and 37 (± 0.82) min and square weighted mean chord lengths are 64.08 (± 3.18), 52.36 (± 5.27) and 42.18 (± 4.61) µm when PLGA Resomer® RG503H, RG502H and RG752H were used respectively. Larger square weighted mean chord length of PLGA polymeric microparticles gave lower chord counts. PLGA RG752H microparticles gave smallest square weighted mean chord length and the chord counts was the highest. The CLDs measured by FBRM showed that a larger particle size mean gave longer CLD and a lower peak of particle number. SEM data revealed that the morphology of microparticles was influenced by type and physical properties of polymer. CONCLUSIONS: FBRM can be employed for online monitoring of the shift in the microparticle CLD and detect transformation of the emulsion droplets into solid microparticles during the solvent evaporation process. The microparticle CLD and transformation process were strongly influenced by polymer type.

Impact of dispersion time interval and particle size on release profiles of propranolol HCl and carbamazepines from microparticle blends system.

The objective of this study was to investigate the effect of dispersion time interval (DTI) on physicochemical properties of drug following the incorporation of propranolol HCl (Pro) and carbamazepine (CBZ) within ethyl cellulose (EC) microparticle blends using solvent evaporation method. The first Pro emulsion and second CBZ oil phase were dispersed in an external aqueous phase, with DTI of 0 and 60 min. The morphology of microparticle blends were characterized by SEM. The particle size mean of the emulsion droplets/hardened microparticles were monitored by FBRM. Encapsulation efficiency (EE) and in vitro drug release were also investigated. The resulting microparticle blends were spherical and formed two populations. The particle size mean of microparticle blends ranged from 113.27 µm to 122.42 µm. The EE was 77.28% to 78.64% for Pro and 96.48% to 98.64% for CBZ. FBRM studies showed that the size of microparticle blend prepared as W/O/W (Pro) and O/W (CBZ) system with DTI of 60 min and stirring time 4 h were larger than those prepared with DTI of 0 min. In vitro drug release studies after 28 days that revealed the CBZ release (58.72%) was faster than Pro release (43.16%). Investigation on surface morphology by SEM showed that the second drug CBZ which added as the oil phase in the W/O/W emulsion system had blocked the pores on the surface Pro microparticles prepared from the first primary emulsion, therefore affecting the drug release. This blocking effects of second drug (CBZ) on first emulsion microparticles (Pro) depended on the DTI. This phenomenon is only applicable if the first primary emulsion is W/O/W system.

Combination of co-crystal and nanocrystal techniques to improve the solubility and dissolution rate of poorly soluble drugs.

PURPOSE: Solubility and dissolution rate are essential for the oral absorption and bioavailability of poorly soluble drugs. The aim of this study was to prepare nano-co-crystals by combination of nanocrystal and co-crystal technologies, and investigate its effect, in situ, on increased kinetic solubility and dissolution rate. METHODS: Co-crystals of itraconazole-fumaric acid, itraconazole-succinic acid, indomethacin-saccharin and indomethacin-nicotinamide were prepared and nano-sized by wet milling. The particle size and solid state of the co-crystals were characterized by optical microscope, LD, PCS, DSC and XRPD before and after milling. RESULTS: 300-450 nm sized nano-co-crystals with a stable physical solid state were successfully prepared. Nano-co-crystals exhibited a lower crystallinity reduction than nanocrystals after wet milling. The particle size effect on the kinetic solubility of co-crystals was analysed for macro-, micro- and nano-co-crystals with in situ kinetic solubility studies. The maximum kinetic solubility of nano-co-crystals increased with excess conditions until a plateau. The highest increase was obtained with itraconazole-succinic acid nano-co-crystals with a kinetic solubility of 263.5 ± 3.9 µg/mL which was 51.5 and 6.6 times higher than the solubility of raw itraconazole and itraconazole-succinic acid co-crystal. CONCLUSIONS: The synergistic effect of nanocrystals and co-crystals with regard to increased kinetic solubility and dissolution rate was proven. The combination of the advantages of nanocrystals and co-crystals is a promising formulation strategy to increase both the solubility and dissolution rate of poorly soluble drugs.

Incorporation of itraconazole nano-co-crystals into multiparticulate oral dosage forms.

Limited research has been performed on the downstream processing of nano-co-crystal suspensions into solid oral dosage forms. The objectives of this study were to evaluate the impact of three downstream processes (wet granulation, spray granulation and bead layering) on the performance of itraconazole-succinic acid (ITZ-SUC) nano-co-crystal suspension. An optimized ITZ-SUC nano-co-crystal suspension mixed with HPMC E5 was utilized for the downstream processing. The suspension was converted in the solid state either by wet or spray granulation (with microcrystalline cellulose or lactose as substrates) or by layering onto microcrystalline cellulose and sugar beads. The multiparticulate solid dosage forms were characterized by optical microscopy, differential scanning calorimeter (DSC), X-ray powder diffraction (XRPD) and in situ dissolution studies. Spray granulation and bead layering resulted in less particle aggregation, a faster dissolution rate, and higher kinetic solubility when compared to wet granulation. ITZ-SUC nano-co-crystals spray granulated with lactose resulted in higher kinetic solubility profiles compared to microcrystalline cellulose granules. The type of bead core had no impact on the dissolution behavior. A slower dissolution and decreased kinetic solubility were observed with increasing drug loading for sprayed granules when microcrystalline cellulose was used as substrate. All dosage forms were stable under accelerated storage conditions (40 °C/75% RH) when blistered. Nano-co-crystals incorporated in granules were less stable than layered beads under non-blistered condition. Nano-co-crystals layered sugar beads are an interesting alternative to amorphous solid dispersion; a comparable kinetic solubility but a faster drug release were achieved. This study identified bead layering as a superior downstream process approach for incorporating ITZ-SUC nano-co-crystals into an oral solid dosage form without compromising drug dissolution.

Kinetic solubility improvement and influence of polymers on controlled supersaturation of itraconazole-succinic acid nano-co-crystals.

Nano-co-crystals enhance the solubility and dissolution rate of poorly soluble drugs. The objective of this study was to obtain a better understanding of the dissolution process of nano-co-crystals and of the precipitation inhibition by various polymers. Itraconazole-succinic acid (ITZ-SUC) nano-co-crystal was chosen as model drug formulation to investigate the supersaturation and precipitation inhibition capabilities of various polymers (HPMC E5, HPMC E50, HPMCAS, HPC-SSL, PVPK30 and PVPVA64). The kinetic concentration-time profiles of nano-co-crystal were measured under non-sink conditions with in situ UV-VIS spectroscopy. HPMC E5 performed best by achieving the greatest extended supersaturation/precipitation inhibition. The precipitation inhibition capacity of HPMC E5 was proportional to its concentration. The maximum achievable supersaturation was proportional to the dissolution rate which can be modulated by the rate of supersaturation generation (i.e., addition rate or dose). Supersaturation could be prolonged significantly resulting in 2-5-fold increased area under the dissolution curves compared to nano-co-crystals alone. This effect was limited by a critical excess of undissolved particles with high specific surface area which acted as crystallization seeds resulting in faster precipitation. The study highlighted that a faster dissolution rate and the use of precipitation inhibitors were two key factors determining the extent and time of supersaturation of nano-co-crystals.

Real-time particle size analysis using focused beam reflectance measurement as a process analytical technology tool for continuous microencapsulation process.

The online real-time particle size analysis of the microencapsules manufacturing process using the continuous solvent evaporation method was performed using focused beam reflectance measurement (FBRM). In this paper, we use FBRM measurements to investigate the effects of polymer type and compare the size distributions to those obtained using other sizing methods such as optical microscope and laser diffraction. FBRM was also utilized to measure the length-weighted chord length distribution (CLD) and particle size distribution (PSD) online during particle solidification, which could not be done with laser diffraction or nested sieve analysis. The chord lengths and CLD data were taken at specific times using an online FBRM probe mounted below the microparticle. The timing of the FBRM determinations was coordinated with the selection of microparticle samples for particle size analysis by optical microscope and laser diffraction calculation as a reference. For all three produced batches tested, FBRM, laser diffraction, and sieve analysis yielded similar results. Hardening time for the transformation of emulsion droplets into solid microparticles occurred within the first 10.5, 19, 25, 30, and 55 min, according to FBRM results. The FBRM CLDs revealed that a larger particle size mean resulted in a longer CLD and a lower peak of particle number. The FBRM data revealed that the polymer type had a significant impact on microparticle CLD and the transformation process.

Gel Strength of Hydrophilic Matrix Tablets in Terms of In Vitro Robustness.

PURPOSE: The purpose of this study was to correlate the gel strength of swollen matrix tablets with their in vitro robustness against agitation intensity and applied mechanical forces. Five commercial products, i.e. Glucophage®, Alfuzosin®, Tromphyllin®, Preductal® MR and Quetiapin® formulated as water-soluble/erodible matrix tablets were investigated. METHODS: Effect of agitation speed (50-150 rpm) on drug release, hydration/erosion and gel strength was investigated using USP paddle apparatus II. The gel strength of matrix tablets during dissolution at different conditions was characterized by a texture analyzer. RESULTS: Commercial tablets formulated with HPMC of higher viscosity, such as K15M or K100M, demonstrated the gel strength in swollen state >0.02 MPa. In this case, the release mechanism was predominantly diffusional and, therefore, not affected by stirring speed and mechanical stress. In contrast, the Quetiapin® matrix tablet, formulated with HPMC K 4 M in amount of approx. 25%, demonstrated the gel strength dropped below 0.02 MPa after 6 h of release. In this case, the drug was predominantly released via erosional mechanism and very susceptible to stirring speed. CONCLUSION: Sufficient gel strength of swollen tablets is an important prerequisite for unchanged in vitro performance in consideration of mechanical stress.

Data on the application of the focused beam reflectance measurement (FBRM): A process parameters dataset for the ethyl cellulose (EC) microparticles preparation by the solvent evaporation method.

The data article refers to the paper "Effect of solvent type on preparation of ethyl cellulose microparticles by solvent evaporation method with double emulsion system using focused beam reflectance measurement" [1]. Data presented here include the effect of solvent type, method of emulsification (an oil-in-water (O/W) or a water-in-oil-in-water (W/O/W)), external aqueous phase volume, stirring speed and ethyl cellulose concentration on the preparation of ethyl cellulose microparticles. Data also refer to the effect of above mentioned factors on the solidification rate, hardening time, particle size, particle size mean, chord length distribution (CLD) and chord count of microparticles. Additionally, data exhibit process parameters when emulsion droplets transformed into solid microparticles during fabrication. The transformation of the emulsion droplets into solid microparticles occured within the first 10, 10.5, 12 and 60 minutes (O/W), and the first 12, 11.5, 10 and 90 minutes (W/O/W) when dichloromethane/methanol (1:1), dichloromethane, ethyl acetate and chloroform were used respectively. Either in O/W and W/O/W emulsion system, Chloroform gave smallest square weighted mean chord length. In contrast, its chord counts was not to be the highest.

Nanocrystals for Improved Drug Delivery of Dexamethasone in Skin Investigated by EPR Spectroscopy.

Nanocrystals represent an improvement over the traditional nanocarriers for dermal application, providing the advantages of 100% drug loading, a large surface area, increased adhesion, and the potential for hair follicle targeting. To investigate their advantage for drug delivery, compared to a base cream formulation, dexamethasone (Dx), a synthetic glucocorticoid frequently used for the treatment of inflammatory skin diseases, was covalently linked with the paramagnetic probe 3-(carboxy)-2,2,5,5-tetramethyl-1-pyrrolidinyloxy (PCA) to DxPCA. To investigate the penetration efficiency between these two vehicles, electron paramagnetic resonance (EPR) spectroscopy was used, which allows the quantification of a spin-labeled drug in different skin layers and the monitoring of the drug release. The penetration behavior in excised healthy and barrier-disrupted porcine skin was monitored by EPR, and subsequently analyzed using a numerical diffusion model. As a result, diffusion constants and free energy values in the different layers of the skin were identified for both formulations. Dx-nanocrystals showed a significantly increased drug amount that penetrated into viable epidermis and dermis of intact (factor 3) and barrier-disrupted skin (factor 2.1) compared to the base cream formulation. Furthermore, the observed fast delivery of the spin-labeled drug into the skin (80% DxPCA within 30 min) and a successive release from the aggregate unit into the viable tissue makes these nanocrystals very attractive for clinical applications.

Quantification of porogen effect on the drug release from single- and multi-layered ethylcellulose coated pellets containing single or combined drugs.

The aim of this work was to develop a mathematical model to estimate the drug release from a conventional single-compartment reservoir pellet and extend its applicability to multi-compartment reservoir pellets. Conventional pellets were prepared by layering the drug onto starter-core then applying various ethylcellulose/HPC coatings for drug release control. Multi-layered pellets comprised a first drug layer of propranolol HCl (D1) followed by a first controlled release coating (C1) and consecutively a second drug layer of carbamazepine or caffeine (D2) and then a second controlled-release coating (C2). Drug release from single- and multi-compartment pellets generally increased with an increase of the water-soluble HPC in the coatings. The response described a sigmoidal curve, which agreed with a cumulative normal distribution function. The developed mathematical model facilitated quantification of the drug release of pellets as a function of the porogen content and the coating level. Additionally, the model was applied successfully in multi-compartment pellets to calculate theses effects on the release of drugs with a broad range of aqueous solubility.

Evaluation of manufacturing process parameters causing multilayer tablets delamination.

The aim of this study was to evaluate the influence of tableting process parameters, i.e. turret rotation speed, pre-compaction and main compaction pressures, and their interactions on layer adhesion of bilayer tablets. The elastic recovery after compaction was used as estimation for the elasticity of the material. Three potential pharmaceutical formulations were evaluated as combinations of immediate (microcrystalline cellulose, lactose, calcium phosphate, pregelatinized starch) and controlled drug release excipients (ethyl cellulose, hydroxypropyl methylcellulose, polyvinyl acetate/polyvinylpyrrolidone). A 3-levels 3-factors central composite Design of Experiment was performed on each formulation, with layer adhesion selected as response. A custom-made shear test was used to determine the tablet tendency to delaminate. Main compaction and turret rotation speed were the most important parameters to be optimized during tablet manufacturing. Main compaction was the principal parameter leading to delamination in case of formulations with plastic materials, particularly at high pressures where the difference in elasticity of excipients had a major impact and was followed by turret rotation speed. The rotation speed did not have an effect on layer adhesion in the case of formulations with brittle excipients.

Evaluation of Hydrogenated Soybean Phosphatidylcholine Matrices Prepared by Hot Melt Extrusion for Oral Controlled Delivery of Water-Soluble Drugs.

The aims of this study were to prepare hydrogenated soybean phosphatidylcholine (HSPC) matrices by hot melt extrusion and to evaluate resulting matrix potential to extend drug release in regard to drug loading and solubility for oral drug delivery of water-soluble drugs. The liquid crystalline nature of HSPC powder allowed its extrusion at 120°C, which was below its capillary melting point. Model drugs with a wide range of water solubilities (8, 20 and 240 mg/mL) and melting temperatures (160-270°C) were used. Extrudates with up to 70% drug loading were prepared at temperatures below the drugs' melting points. The original crystalline state of the drugs remained unchanged through the process as confirmed by XRPD and hot-stage microscopy. The time to achieve 80% release (t80) from extrudates with 50% drug loading was 3, 8 and 18 h for diprophylline, caffeine and theophylline, respectively. The effect of matrix preparation method (extrusion vs. compression) on drug release was evaluated. For non-eroding formulations, the drug release retarding properties of the HSPC matrix were mostly not influenced by the preparation method. However, with increasing drug loadings, compressed tablets eroded significantly more than extruded matrices, resulting in 2 to 11 times faster drug release. There were no signs of erosion observed in extrudates with different drugs up to 70% loadings. The mechanical robustness of HSPC extrudates was attributed to the formation of a skin-core structure and was identified as the main reason for the drug release controlling potential of the HSPC matrices produced by hot melt extrusion.

pH-sensitive Eudragit® L 100 nanoparticles promote cutaneous penetration and drug release on the skin.

Nanoparticles (NPs) are promising carriers for dermal and transdermal drug delivery. However, the underlying dynamics of drug release from the NPs, especially, how the physiological changes of diseased skin influence the drug release, remain poorly understood. We utilized electron paramagnetic resonance (EPR) and confocal laser scanning microscopy (CLSM) to comprehensively investigate the penetration behavior of a spin-labeled dexamethasone (DxPCA)-loaded pH-sensitive Eudragit® L 100 NP on intact and barrier-disrupted skins. The EPR investigation showed that a rapid in vitro DxPCA release from the NPs was triggered above pH 5.9. It also demonstrated that the NPs considerably improved the cutaneous penetration of the model drug in comparison to a commercial cream. Besides, as compared to the intact skin, a faster drug release and a higher drug penetration into the viable skin layers were obtained with barrier-disrupted skin. In accordance, CLSM studies confirmed that the NPs enhanced the penetration of the lipophilic model drug Nile red (NR) across the skin, whose penetration depth into glabrous skin was 160 µm. Moreover, a significant transfollicular penetration of NR from the NPs was observed. In conclusion, the pH-sensitive Eudragit® L 100 NPs improved the cutaneous penetration and controlled the release of a lipophilic drug, especially on barrier-disrupted skin. This may allow targeted drug delivery to lesional skin, avoiding side effects.

Impact of change of matrix crystallinity and polymorphism on ovalbumin release from lipid-based implants.

The objectives of this study were to prepare lipid-based implants by hot melt extrusion (HME) for the prolonged release of ovalbumin (OVA), and to relate protein release to crystallinity and polymorphic changes of the lipid matrix. Two lipids, glycerol tristearate and hydrogenated palm oil, with different composition and degree of crystallinity were studied. Solid OVA was dispersed within the lipid matrixes, which preserved its stability during extrusion. This was partially attributed to a protective effect of the lipidic matrix. The incorporation of OVA decreased the mechanical strength of the implants prepared with the more crystalline matrix, glycerol tristearate, whereas it remained comparable for the hydrogenated palm oil because of stronger physical and non-covalent interactions between the protein and this lipid. This was also the reason for the faster release of OVA from the glycerol tristearate matrix when compared to the hydrogenated palm oil (8 vs. 28 weeks). Curing induced and increased crystallinity, and changes in the release rate, especially for the more crystalline matrix. In this case, both an increase and a decrease in release, were observed depending on the tempering condition. Curing at higher temperatures induced a melt-mediated crystallization and solid state transformation of the glycerol tristearate matrix and led to rearrangements of the inner structure with the formation of larger pores, which accelerated the release. In contrast, changes in the hydrogenated palm oil under the same curing conditions were less noticeable leading to a more robust formulation, because of less polymorphic changes over time. This study helps to understand the effect of lipid matrix composition and crystallinity degree on the performance of protein-loaded implants, and to establish criteria for the selection of a lipid carrier depending on the release profile desired.

Improving release completeness from PLGA-based implants for the acid-labile model protein ovalbumin.

The objectives of this study were to assess the feasibility of hot melt extrusion (HME) for the preparation of PLGA-based ovalbumin-loaded implants as well as to characterize and improve protein release from the implants. Ovalbumin (OVA) was stable during extrusion, which was attributed to a protective effect of the biodegradable matrix. OVA release was characterized by a low burst, a slow release up to day 21, which plateaued thereafter resulting in incomplete release for all evaluated protein loadings. Release incompleteness was accompanied by the formation of an insoluble residual mass. Further characterization of this mass indicated that it consisted of non-covalent protein aggregates and polymer, where ovalbumin was ionically bound as the pH inside the degrading matrix decreased below the pI of the protein. Although higher protein release was obtained with the inclusion of weak bases because of their neutralizing effect, OVA aggregation and release incompleteness were not fully avoided. With the use of shellac, a well-known enteric and biocompatible polymer, as protective excipient, a distinct late release phase occurred and release completeness was increased to more than 75% cumulative release. Shellac apparently protected the protein against the acidic microclimate due to its low solubility at low pH. Protected OVA was thus released once the pH increased due to a declining PLGA-oligomer formation. The result was a triphasic release profile consisting of an initial burst, a slow diffusion phase over about 7 weeks, and an erosion-controlled dissolution phase over the next 3 weeks. An acid-labile protein like OVA was thus feasibly protected from interactions with PLGA and its degradation products, resulting in a controlled delivery of more than 85% of the original payload.

Preparation of amorphous indomethacin nanoparticles by aqueous wet bead milling and in situ measurement of their increased saturation solubility.

The aim of this study was to prepare amorphous indomethacin nanoparticles in aqueous media and to determine in situ their increased saturation solubility and dissolution rate. Drug nanosuspensions with a Z-average of ∼300 nm were prepared by wet media milling and afterwards freeze-dried. The drug solid state was analyzed by DSC, XRD and FTIR before and after the milling process. Milling of amorphous indomethacin with polyvinylpyrrolidone (PVP) as stabilizer resulted in an amorphous nanosuspension which could not be redispersed in the nanosize range after freeze-drying. The combination of PVP and poloxamer 407 resulted in crystalline nanoparticles: poloxamer 407, a polymer with high molecular weight, competed with PVP for surface coverage, and hindered the interaction between PVP and indomethacin. This indicated the importance of sufficient drug-PVP interactions on the drug particle surface for amorphous state stabilization. Redispersable amorphous indomethacin nanoparticles were obtained by combining the anti-recrystallization effect of PVP with the particle size stabilization provided by sodium dodecyl sulfate. Solubility studies were performed in situ. The solubility of crystalline micronized indomethacin of 6.7 ±â€¯1.3 µg/mL was increased up to 17.3 ±â€¯2.8 µg/mL by its amorphization, with a factor of increase of 2.6. Indomethacin amorphization increased its dissolution rate by a factor of 30. Indomethacin nanocrystals resulted in an increased solubility of 2.6 times, with a solubility of 17.2 ±â€¯0.4 µg/mL. The highest increase was obtained with amorphous indomethacin nanoparticles with a solubility of 35 ±â€¯1.6 µg/mL and 5.2 times higher than the solubility of the original indomethacin. Amorphous indomethacin nanoparticles resulted in the highest dissolution rate, which increased from 0.003 µg/(mL s) to 2.328 µg/(mL s). The synergistic effect obtained by the combination of nanosize and amorphous solid state was demonstrated.

Saturated phosphatidylcholine as matrix former for oral extended release dosage forms.

The aim of this study was to evaluate the suitability of saturated phosphatidylcholine (Phospholipon® 90H) as extended release excipient in matrix tablets for three model drugs with different aqueous solubility (theophylline, caffeine and diprophylline). The tablets could be prepared by direct compression because of the favorable phospholipid powder flow properties (Carr's index: 12.64 and angle of repose: 28.85) and good compactibility. Tablets of low porosity were formed already at low pressure of 40MPa and with drug loadings up to 70% due to high plasticity of the phospholipid. Extended drug release was achieved with the drugs of different solubility and at various drug loadings. For example, the caffeine release time (t80%) from 8mm tablets ranged from 1.5h to 18h at 70% and 10% drug loading, respectively. The drug release was governed by diffusion and could therefore be modelled by Fick's law of diffusion. Drug release profiles were thus a function of drug solubility, drug loading and tablet dimension. Matrix tablets of caffeine (20% drug loading) showed robust dissolution with regard to agitation (50-100rpm) and ionic strength of the release media (100-600 mOsmol/kg). Caffeine release was pH-dependent with a faster drug release at acidic pH, which was attributed to a protonization of the phosphatidyl group of the matrix-former and thus a higher hydrophilicity.