Enhanced Release of Indomethacin from PVP/Stearic Acid Microcapsules Prepared Coupling Co-freeze-drying and Ultrasound Assisted Spray-congealing Process

Purpose Fast releasing indomethacin microparticles were prepared encapsulating co-freeze-dried indomethacin/poly(vinylpyrrolidone) particles (IMC/PVP) into molten stearic acid (SA), by means of a ultrasonic spray-congealing technique. Materials and Methods IMC particles were suspended in a PVP aqueous solution and the system was then freeze-dried. A suspension was prepared from the co-freeze dried IMC/PVP powder into molten SA that was then atomized into small droplets using ultrasound. Solidification in air produced microparticles having regular macroscopic morphology and coated by a SA thin external film. At each step the material was examined by electron microscopy (SEM and EDAX), thermal analysis and dissolution tests. Results SEM examination did not reveal a smooth surface, differently from what was observed in the case of pure SA microparticles, obtained by the same method. The external film was found to uniformly protect the internal core of the capsules: EDAX spectra demonstrated the absence of the IMC identifying Cl peak on the surface, when the spectra were carried out at low energy of the electron beam. HPLC analysis verified that the drug was uniformly distributed inside the final microparticles at all the size fractions considered. Thermal microscopy confirmed the presence of IMC crystals, after the fusion of the external SA coat. Conclusions The behavior of microparticles to dissolution at pH 7.4 was superior to that of pure drug, reaching 70% of the drug released, after 20 min. Finally the system examined is stable towards aging: no difference in the dissolution behavior could be detected for the final microparticles after 8 months at 25°C.     

Solid dispersion particles of amorphous indomethacin with fine porous silica particles by using spray-drying method

The solid dispersion particles of indomethacin (IMC) were prepared with different types of silica, non-porous (Aerosil 200) or porous silica (Sylysia 350) by using spray-drying method. Powder X-ray diffraction analysis showed that IMC in solid dispersion particles is in amorphous state irrespective of the type of silica formulated. In DSC analysis, the melting peak of IMC in solid dispersion particles with Sylysia 350 shifted to lower temperature than that in solid dispersion particles with Aerosil 200 although the peak of each solid dispersion particles was much smaller than that of original IMC crystals. Dissolution property of IMC was remarkably improved by formulating the silica particles to the solid dispersion particles. In comparing the effect of the type of the silica particles, the dissolution rate of solid dispersion particles with Sylysia 350 was faster than that with Aerosil 200. The formulation amount of IMC did not affect on the amorphous state of IMC in the resultant solid dispersion particles in powder X-ray diffraction patterns. However, the area of the melting peak of IMC in the solid dispersion particles increased and an exothermic peak owing to recrystallization was observed with increasing the IMC content in the DSC patterns. The dissolution rate of IMC from the solid dispersion particles with Sylysia 350 was faster than that of Aerosil 200 irrespective of IMC content. In stability test, amorphous IMC in the solid dispersion particles with each silica particles did not crystallize under storing at severe storage conditions (40 degrees C, 75% RH) for 2 months, while amorphous IMC without silica easily crystallized under same conditions.     

The physicochemical characteristics and bioavailability of indomethacin from beta-cyclodextrin, hydroxyethyl-beta-cyclodextrin, and hydroxypropyl-beta-cyclodextrin complexes

In an effort to improve the bioavailability of the insoluble drug indomethacin, three complexes were prepared with indomethacin and the soluble complexing agents β-, hydroxyethyl-β-, and hydroxypropyl-β-cyclodextrin. The indomethacin content was similar among the complexes (P≤0.05). To confirm complex formation, each complex was characterized by ultraviolet, infrared, nuclear-magnetic resonance, powder X-ray diffraction, and differential-scanning calorimetry techniques. Powder diffraction studies show the β-cyclodextrin complex was polycrystalline, and the hydroxyethyl- and hydroxypropyl-β-cyclodextrin complexes were amorphous. Phase-solubility analysis confirmed the formation of complexes and suggested the three complexes were bound similarly. Solubility studies show complexation increased indomethacin solubility, and the hydroxyethyl- and hydroxypropyl-β-cyclodextrin complexes were more soluble than the β-cyclodextrin complex in 0.1N hydrochloric acid and distilled water. Dosage forms were prepared by encapsulating the complexes without the addition of excipients. Dissolution studies show the encapsulated β- and hydroxyethyl-β-cyclodextrin complexes had superior dissolution when compared to the hydroxypropyl-β-cyclodextrin and Indocin^® (50 mg) capsules. Bioavailability studies were performed by administering the indomethacin complex or Indocin capsules to male-albino, New Zealand rabbits. Indomethacin plasma-time concentration data fit best to a compartment-independent model for all capsule formulations. Bioavailability comparisons by ANOVA show no significant difference (P≤0.10) in the peak-plasma time and peak concentration among the capsule formulations. The area-under-the-curve for the β-cyclodextrin complex capsules was found to be significantly higher (P≤0.10) than all other capsule formulations. In conclusion, the bioavailabilty of indomethacin was improved by complexation with only β-cyclodextrin. No correlations were found among the bioavailability, solubility, and dissolution results.     

Characterization of physicochemical properties of naproxen systems with amorphous beta-cyclodextrin-epichlorohydrin polymers

Ground mixtures of naproxen with amorphous β-cyclodextrin-epichlorohydrin soluble (βCd-EPS) or insoluble cross-linked (βCd-EPI) polymers were investigated for both solid phase characterization (Differential Scanning Calorimetry, powder X-ray Diffractometry) and dissolution properties (dispersed amount method). The effect of different grinding conditions and of drug-to-carrier ratio was also evaluated. Co-grinding induced a decrease in drug crystallinity to an extent which depended on the grinding time, and was most pronounced for the cross-linked insoluble polymer, particularly in combinations at the lowest drug content. Both cyclodextrin polymers were more effective in improving the naproxen dissolution properties, not only than the parent βCd but also than hydroxyalkyl-derivatives, and their performance was almost comparable to that of methyl-derivatives, previously found as the best carriers for naproxen. Dissolution efficiencies of naproxen from physical mixtures with βCd-EPS, thanks to the high water solubility of this Cd-derivative, were up to three times higher than those from the corresponding products with βCd-EPI. However this difference in their performance became much less evident in co-ground products and tended to progressively diminish with increasing the polymer content in the mixture, according to the better amorphizing power shown by βCd-EPI during the co-grinding process. The 10/90 (w/w) drug–carrier co-ground products exhibited the best dissolution properties, giving dissolution efficiencies about 30 times higher than that of naproxen alone.     

Differences in dissolution behavior in a phagolysosomal simulant fluid for single-constituent and multi-constituent materials associated with beryllium sensitization and chronic beryllium disease.

Particle dissolution within macrophage phagolysosomes is hypothesized to be an important source of dissolved beryllium for input to the cell-mediated immune reaction associated with development of beryllium sensitization and chronic beryllium disease (CBD). To better understand the dissolution of beryllium materials associated with elevated prevalence of sensitization and CBD, single-constituent (beryllium oxide (BeO) particles sampled from a screener operation, finished product BeO powder, finish product beryllium metal powder) and multi-constituent (particles sampled from an arc furnace during processing of copper-beryllium alloy) aerosol materials were studied. Dissolution rates were measured using phagolysosomal simulant fluid (PSF) in a static dissolution technique and then normalized to measured values of specific surface area to calculate a chemical dissolution rate constant (k) for each material. Values of k, in g/(cm2 day), for screener BeO particles (1.3 +/- 1.9 x 10(-8)) and for BeO powder (1.1 +/- 0.5 x 10(-8)) were similar (p = 0.45). The value of k observed for beryllium metal powder (1.1 +/- 1.4 x 10(-7)) was significantly greater than observed for the BeO materials (p < 0.0003). For arc furnace particles, k (1.6 +/- 0.6 x 10(-7)) was significantly greater than observed for the BeO materials (p < 0.00001), despite the fact that the chemical form of beryllium in the aerosol was BeO. These results suggest that dissolution of beryllium differs among physicochemical forms of beryllium and direct measurement of dissolution is needed for multi-constituent aerosol. Additional studies of the dissolution behavior of beryllium materials in a variety of mixture configurations will aid in developing exposure-response models to improve understanding of the risk of beryllium sensitization and CBD.     

Influence of formulation and process parameters on the release characteristics of ethylcellulose sustained-release mini-matrices produced by hot-melt extrusion

Mini-matrices (multiple unit dosage form) with release-sustaining properties were developed by hot-melt extrusion (cylindrical die: 3 mm) using metoprolol tartrate as model drug and ethylcellulose as sustained-release agent. Dibutyl sebacate was selected as plasticizer and its concentration was optimized to 50% (w/w) of the ethylcellulose concentration. Xanthan gum, a hydrophilic polymer, was added to the formulation to increase drug release. Changing the xanthan gum concentration modified the in vitro drug release: increasing xanthan gum concentrations (1%, 2.5%, 5%, 10% and 20%, w/w) yielded a faster drug release. Zero-order drug release was obtained at 5% (w/w) xanthan gum. Using kneading paddles, smooth extrudates were obtained when processed at 60 °C. At least one mixing zone was required to obtain smooth and homogeneous extrudates. The mixing efficacy and drug release were not affected by the number of mixing zones or their position along the extruder barrel. Raman analysis revealed that metoprolol tartrate was homogeneously distributed in the mini-matrices, independent of screw design and processing conditions. Simultaneously changing the powder feed rate (6–25–50 g/min) and screw speed (30–100–200 rpm) did not alter extrudate quality or dissolution properties.     

In vitro study of the pulmonary translocation of nanoparticles: a preliminary study

Recent studies indicate that inhaled ultrafine particles can pass into the circulation. To study this translocation in an in vitro model three types of pulmonary epithelial cells were examined. The integrity of the cell monolayer was verified by measuring the transepithelial electrical resistance (TEER) and passage of sodium fluorescein. TEER was too low in A549 cells. In these preliminary experiments, TEER values of 1007 ± 300 and 348 ± 62 Ω cm² were reached for the Calu-3 cell line, using permeable membranes of 0.4 and 3 μm pore size, respectively. Growing primary rat type II pneumocytes on 0.4 μm pores, a TEER value of 241 ± 90 Ω cm² was reached on day 5; on 3 μm pores, no acceptable high TEER value was obtained. Translocation studies were done using 46 nm fluorescent polystyrene particles. When incubating polystyrene particles on membranes without a cellular monolayer, significant translocation was only observed using 3 μm pores: 67.5% and 52.7% for carboxyl- and amine-modified particles, respectively. Only the Calu-3 cell line was used in an initial experiment to investigate the translocation: on 0.4 μm pores no translocation was observed, on 3 μm pores 6% translocation was observed both for carboxyl- and amine-modified particles.     

Theophylline particle design using chitosan by the spray drying

Solid dispersions of theophylline with chitosan as a carrier were prepared using a spray-drying method. Chitosan dissolved in an acid solution forms a gel, but it does not dissolve in an alkaline solution. Therefore, drugs which form composite particles with chitosan would gradually be released in an acid solution, and are expected to have considerably sustained release in an alkaline solution. In this study, we aimed to apply this ability to sustained release pharmaceutics.

In this study, we used theophylline as a model drug and chitosan as a carrier. Mixtures of chitosan and the drug in prescribed ratios were dissolved in an acid solution.

The physicochemical properties of the solid dispersions obtained were investigated by powder X-ray diffraction, differential scanning calorimetry, and dissolution rate analyses, with a view to clarify the effect of crystallinity on the dissolution rate. Furthermore, the interaction between the drug and the carrier was investigated by FT-IR analysis.

The powder X-ray diffraction intensity of the drug in the spray-dried samples decreased with an increase in chitosan contents, which also caused changes from crystalline to amorphous forms. These results indicated that the system formed a solid dispersion. The dissolution profiles of the drug from the physical mixtures and solid dispersions were almost the same at pH 1.2. However, at pH 6.8, the release from the solid dispersions was sustained more than that from the physical mixtures. The FT-IR spectroscopy for the theophylline solid dispersions suggested that the carbonyl group of theophylline and the amino group of chitosan formed a hydrogen bond.

Mass median aerodynamic diameter (MMAD) was measured by using a cascade impactor to evaluate the possibility of solid dispersions as dry powder inhalations. The MMAD of the spray-dried theophylline-chitosan systems were 4.5–5.0 μm. The results suggested that the spray-drying method is usefull to produce dry powders for inhalation.     

Understanding improved dissolution of indomethacin through the use of cohesive poorly water‐soluble aluminium hydroxide: Effects of concentration and particle size distribution

The objective of this study was to explore the effects of concentration and particle size distribution of an added poorly water‐soluble inorganic salt, aluminium hydroxide, on the dissolution of a poorly water‐soluble drug, indomethacin (IMC), from lactose interactive mixtures. Dissolution was studied using the United States Pharmacopeia paddle method in buffer pH 5.0 and the data most aptly fitted a bi‐exponential dissolution model which represented dissolution occurring from dispersed and agglomerated particles. The dispersion of IMC mixtures was measured in dissolution media under non‐sink conditions by laser diffraction. The dissolution of IMC increased as a function of the concentration of aluminium hydroxide (5–20%) added to the mixtures. Increasing the proportion of larger particles of the cohesive aluminium hydroxide increased the dissolution rate of IMC. The enhanced dissolution was attributed to increases in both the dissolution rate constant and initial concentration of dispersed particles. Mechanistically, the aluminium hydroxide was found to facilitate the detachment of IMC particles from the carrier surface, forming a complex interactive mixture that more readily deagglomerated than the cohesive drug agglomerates. The outcomes of this work would therefore allow more careful control and selection of the excipient specifications in producing solid dosage formulations with improved dissolution of poorly water‐soluble drugs. © 2011 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:4269–4280, 2011     

Influence of sulfobutyl ether beta-cyclodextrin (Captisol) on the dissolution properties of a poorly soluble drug from extrudates prepared by hot-melt extrusion

The aim of this study was to investigate the influence of sulfobutyl ether β-cyclodextrin (SBE₇-β-CD; Captisol^®) on the dissolution properties of a poorly water-soluble drug from extrudates prepared by hot-melt extrusion. Ketoprofen was employed as a model drug. Extrudates containing the parent β-cyclodextrin (β-CD) were also produced for comparative evaluation to assess the benefits of SBE₇-β-CD. Hot-melt extrudates were produced at 100 °C, which was close to the melting point of ketoprofen. The physiochemical properties and the in vitro drug release properties of ketoprofen from extrudates were investigated and compared with samples prepared by physical mixing, co-grinding, freeze-drying and heat-treatment. The solubilizing effects and the interactions of ketoprofen with SBE₇-β-CD and β-CD were investigated using phase solubility and NMR studies, respectively. The dissolution rate of ketoprofen from samples prepared by hot-melt extrusion with SBE₇-β-CD was significantly faster than both the physical mixture and the hot-melt extrudates prepared with the parent β-CD. Moisture absorption studies revealed that the hygroscopic nature of SBE₇-β-CD led to particle aggregation and a corresponding decrease in drug release rate for all samples. However, the samples prepared by melt extrusion were least affected by exposure to elevated humidity.     

Preparation and characterization of quercetin nanocrystals

This study is to enhance the dissolution rate of a poorly water-soluble drug, quercetin, by fabricating nanocrystals using high-pressure homogenization. The particle size, crystallinity, dissolution, and antioxidant effects of fabricated quercetin nanocrystals have been investigated. Characterization of the original quercetin powder and nanocrystals was carried out by photon correlation spectroscopy (PCS), laser diffraction, scanning electron microscopy, differential scanning calorimetry (DSC), X-ray diffraction, dissolution tester, and so on. A PCS size of about 483 nm was obtained for the nanocrystals after 20 cycles of homogenization at 1500 bar. X-ray diffraction and DSC studies revealed that the lyophilized quercetin nanoparticles were crystalline after high-pressure homogenization. The percent dissolution efficiency, relative dissolution, mean dissolution time, difference factor (f(1)), and similarity factor (f(2)) were calculated for the statistical analysis. It was found that the dissolution of the drug nanocrystals was much higher than that of the pure drug at pH 6.8 and 1.2. The antioxidant activity and reducing power of the quercetin nanocrystals were more effective than the original quercetin.     

Ultrasound-compacted indomethacin/polyvinylpyrrolidone systems: effect of compaction process on particle morphology and dissolution behavior

Indomethacin (IMC)/polyvinylpyrrolidone systems were prepared under different technological conditions, using co-evaporation, kneading, traditional, and ultrasound (US) compaction. The materials thus obtained were milled and sieved and the powders were analyzed by using scanning electron microscopy to evaluate the morphology of the final particles and the fractal dimension of the particle contour. In the case of US-treated particles, scanning electron micrographs suggest that IMC could have partially covered the excipient granule surface, which appears lustrous and smooth, whereas after co-evaporation, the particles display a stratified structure. The external color of the granules, the hot stage microscopy examination, and the absence of the melting peak of the drug in thermograms supports the idea that IMC converts into an amorphous form under US discharge. Each technological treatment performed on the binary mixtures increases the dissolution rate of the drug, with respect to the pure drug and the physical mixture, but to a lesser extent than US compaction. US compaction and co-evaporation produce comparable results in improving the release of the drug. Polyvinylpyrrolidone offers better results than beta-cyclodextrin in promoting the dissolution of IMC, when both systems are compacted under US.     

Chemoinformetrical evaluation of dissolution property of indomethacin tablets by near-infrared spectroscopy

PURPOSE: The purpose of this study was to use near-infrared spectrometry (NIR) with chemoinformetrics to predict the change of dissolution properties in indomethacin (IMC) tablets during the manufacturing process. A comparative evaluation of the dissolution properties of the tablets was performed by the diffused reflectance (DRNIR) and transmittance (TNIR) NIR spectroscopic methods. METHODS: Various kinds of IMC tablets (200 mg) were obtained from a powder (20 mg of IMC, 18 mg of microcrystalline cellulose, 160 mg of lactose, and 2 mg of magnesium stearate) under various compression pressures (60-398 MPa). Dissolution tests were performed in phosphate buffer, and the time required for 75% dissolution (T75) and mean dissolution time (MDT) were calculated. DRNIR and TNIR spectra were recorded, and the both NIR spectra used to establish a calibration model for predicting the dissolution properties by principal component regression analysis (PCR). RESULTS: The T75 and MDT increased as the compression pressure increased, since tablet porosity decreased with increasing pressure. Intensity of the DRNIR spectra of the compressed tablets decreased as the compression pressure increased. However, the intensity of TNIR spectra increased along with the pressure. The calibration models used to evaluate the dissolution properties of tablets were established by using PCR based on both DRNIR and TNIR spectra of the tablets. The multiple correlation coefficients of the relationship between the actual and predictive T75 by the DRNIR and TNIR methods were 0.831 and 0.962, respectively. CONCLUSION: It is possible to predict the dissolution properties of pharmaceutical preparations using both DRNIR and TNIR chemoinformetric methods. The TNIR method was more accurate for predictions of the dissolution behavior of tablets than the DRNIR method.     

Effect of cyclodextrins on the acid hydrolysis of digoxin

The effects of three cyclodextrins (alpha-, beta-, gamma-CyD) on the acid hydrolysis of digoxin were examined. From the high performance liquid chromatographic tracing of each of the four components (digoxin, bisdigitoxoside, monodigitoxoside, digoxigenin) in reaction mixtures, the individual rate constants (K1-K6) were determined by analogue computer simulation. The hydrolysis was suppressed by CyDs in the order of beta-great than gamma-greater than alpha-greater than-CyD, where beta-CyD inhibited the appearance rates of digoxigenin (k3, K5, and K6) significantly. In the dissolution study of digoxin tablets, the increase in dissolution rate and decrease in acid hydrolysis were attained by inclusion complexation. The data are presented suggesting that CyDs are useful for improving the oral bioavailability of digoxin.     

Pharmaceutical and pharmacokinetic characteristics of different types of fenofibrate nanocrystals prepared by different bottom-up approaches

Abstract

Low dissolution rate of a poorly water soluble drug often leads to low and variable oral bioavailability. Formulating drugs as nanocrystals can help to overcome these problems by increasing the solubility and dissolution velocity. But different preparation approaches may result in different nanocrystals with different characteristics. In this study, three types of fenofibrate nanocrystals (FNT-NCs) were prepared by bottom-up methods, antisolvent and thermal precipitation under different conditions. These FNT-NCs were characterized by scanning electron micrography, dissolution testing, differential scanning calorimetry and powder X-ray diffractometry. A significant increase of dissolution rate was observed in the drug nanocrystals compared to the crude FNT powder (from 20% to 80% in 5?min). The crystallinity of the FNT-NCs prepared by antisolvent precipitation increased slightly, while that by thermal precipitation decreased. The oral bioavailability of two types of FNT-NCs prepared by antisolvent precipitation in rats increased notably compared to that of the crude powder (5.5-folds and 5.0-folds, respectively). However, the oral absorption of FNT-NCs prepared by thermal precipitation did not increase, although its dissolution rate was higher than that of the crude powder. In conclusion, different bottom-up methods produce different FNT-NCs with different crystallinity, which results in different oral bioavailability. Namely, a careful study and rational choice on preparation approaches are significant for the nanocrystal techniques.     

Amphiphilic amino acid copolymers as stabilizers for the preparation of nanocrystal dispersion

The recent advance of particle size engineering in nanometer ranges has widened the formulation opportunities of relatively water-insoluble drugs. However, the ‘nanoformulation’ suffers from a lack of systematic understanding about the requirements of polymeric stabilizers. Furthermore, the polymers that can be used for the preparation of nanocrystals are so limited that finding a proper stabilizer for a given formulation is often difficult. In this study, amino acid copolymers whose properties can systematically be tailored are developed, and their morphological and compositional effects are investigated. Copolymers containing lysine (K) as their hydrophilic segments, and phenylalanine (F) or leucine (L) as their hydrophobic segments successfully produce stable nanocrystals (200–300 nm) in water, while copolymers of K and alanine (A) could not generate nanosized particles. Not the morphology but the hydrophobicity of copolymers seems to be a critical parameter in the preparation of drug nanocrystals by wet comminution. The effective stabilization performance of copolymers requires the hydrophobic moiety content to be higher than 15 mol%. Comminution for only 5 min is long enough for nanocrystal preparation, and the crystallinity of drug is found intact after the processing.     

伊曲康唑纳米晶体的制备与表征

目的：制备伊曲康唑纳米晶体并进行药剂学性质表征。方法：采用湿法介质研磨结合冷冻干燥工艺制备伊曲康唑纳米晶体;采用马尔文激光粒度测定仪测定伊曲康唑纳米晶体的粒径和多分散系数（PDI）;采用扫描电镜观察伊曲康唑粒子的形态;采用差示扫描量热法、红外光谱法、X-射线粉末衍射法研究伊曲康唑纳米化前后晶型和化学结构变化情况;采用浆法比较伊曲康唑纳米化前后及市售胶囊在pH 1.2、pH 4.0、pH 6.8的溶液以及水等4种溶出介质中的溶出行为。结果：制备的伊曲康唑纳米晶体平均粒径为317 nm,PDI值0.29;纳米化前后伊曲康唑晶型和化学结构没有发生明显改变;在pH 1.2、pH 4.0、pH 6.8的溶液以及水等4种溶出介质中,药物溶出速率快慢顺序为伊曲康唑纳米晶体> 市售伊曲康唑胶囊> 物理混合物及伊曲康唑原料药。结论：采用湿法介质研磨结合冷冻干燥工艺,可以制备平均粒径小且较为均匀的伊曲康唑纳米晶体;纳米化后伊曲康唑仍为结晶态;制成纳米晶体可以明显改善伊曲康唑的溶出性能,利于改善药物的口服吸收。     

Solid state studies of drug–cyclodextrin inclusion complexes in PEG 6000 prepared by a new method

The melting method was investigated as a possible method for producing drug–cyclodextrin (CD) inclusion compounds in a carrier. Various solid dispersions of -, β- and γ-CD in polyethylene glycol (PEG) 6000 with and without the addition of 5% w/w indomethacin or griseofulvin were prepared using the original components. Characterisations of the samples included X-ray powder diffraction, modulated-temperature differential scanning calorimetry and dissolution tests by the paddle method according to USP XXI standard. Evidence of a complex between indomethacin and β-CD in PEG 6000 was found. An indomethacin–γ-CD complex formed a well defined phase in the PEG carrier, with tetragonal structure and unit cell parameters a=23.885(35) Å and c=23.181(64) Å. No complexation of indomethacin with -CD, or with griseofulvin and β-CD could be detected. It is suggested that competition between PEG and the drug for the binding to different CDs along with varying patterns of water loss from the CDs influence the inclusion reaction. The formation of complexes was accompanied by a decrease in the relative crystallinity of the dispersions. Dissolution tests showed that the CDs have a delaying effect on the release of indomethacin from PEG 6000 in the order -CD<γ-CD≤β-CD.     

Amorphous spironolactone-hydroxypropylated cyclodextrin complexes with superior dissolution and oral bioavailability

Inclusion complex formations of spironolactone (SP) with four cyclodextrins (parent β- and γ-CyDs and hydroxypropylated β- and γ-CyDs) in aqueous solution and in the solid state were investigated by the solubility method, spectroscopic methods, thermal analysis, powder X-ray diffractometry, and cross polarization/magic angle spinning ¹³C-nuclear magnetic resonance spectroscopy. Although the stability constant of the parent CyD complexes was larger than that of the corresponding hydroxypropylated CyD complexes, the solubilizing effect of hydroxypropyl CyDs was greater than that of parent CyDs. The solid complexes of SP were prepared by the spray-drying method in molar ratios of 1:2 and 2:3 (guest/host) with β-CyDs and γ-CyDs, respectively. The CyD complexes maintained an amorphous state for lengthy time periods (over 2 months at 75% relative humidity and 60°C), with the exception of the β-CyD complex which was converted to a crystalline complex after 1 month storage. The dissolution rate of hydroxypropyl CyD complexes was much faster than that of the parent CyD complexes, the rate being in the order of hydroxypropyl-β-CyD ⪢ hydroxypropyl-γ-CyD > γ-CyD > β-CyD > metastable SP forms > stable SP form. Plasma levels of canrenone, a major effective metabolite of SP, were monitored to estimate the absorption-enhancing effect of hydroxypropyl CyDs. The area under the plasma concentration-time curve after oral administration of the hydroxypropyl-β-CyD complex in dogs was 3.6 times that of SP alone, and this enhancement was higher than those of the parent CyD complexes reported previously (Seo, H., Tsuruoka, M., Hashimoto, T., Fujinaga, T., Otagiri, M. and Uekama, K., Enhancement of oral bioavailability of spironolactone by β- and γ-cyclodextrin complexations. Chem. Pharm. Bull., 31 (1983) 286–291).     

Quantitative analysis of amorphous content of lactose using CCD-Raman spectroscopy

A Raman spectroscopy method was developed for the quantification of the amorphous content of lactose. Both physical mixtures and spray-dried samples were used and the results were compared with the IMC determinations. Sample inhomogeneities were averaged out by collecting multiple spectra from each sample, and the total measurement time remained below 10 min due to the high sensitivity of the CCD-Raman spectrometer used in the measurements. The obtained calibration error (SEC) for the physical mixtures was 1.3% (w/w) in the 0–100% amorphous content range and was reduced to 0.2% (w/w) in the 0–10% range of more practical interest. The crystallization heat values of the spray-dried samples showed a linear correlation with the Raman quantifications in the amorphous content range of 0–80%, but saturated over the 80% concentration. This finding suggests a reference value of ca. 60 J/g for the spray-dried samples, instead of the crystallization heat of amorphous lactose (ca. 50 J/g) valid in the IMC determinations of physical mixtures.