Influence of Formulation Factors and Compression Force on Release Profile of Sustained Release Metoprolol Tablets using Compritol? 888ATO as Lipid Excipient

Tablets containing metoprolol succinate and Compritol^® 888ATO in the ratio of 1:2 yielded the desired sustained release profile in phosphate buffer pH 6.8 when evaluated using USP type II paddle apparatus and was selected as the optimized formulation. Robustness of optimized formulation was assessed by studying the effect of factors like varying source of metoprolol succinate and Compritol^® 888ATO, compression force and hydroalcoholic dissolution medium on the release profile. No significant difference (P>0.05) in release profile was observed when metoprolol succinate from three different sources and Compritol^® 888ATO from two different batches were used. Release profile of sustained release tablets of metoprolol succinate in media containing various concentrations of ethanol was comparable with media devoid of ethanol as evaluated by f2 test. This indicated that release profile of sustained release tablets of metoprolol succinate was reliable with no significant change due to variation in source of active pharmaceutical ingredient, particularly due to particle size distribution. Sustained release tablets of metoprolol succinate yielded release pattern within specifications irrespective of presence or absence of ethanol in the medium indicating that release properties of Compritol^® 888ATO matrix are not affected by ethanol. Tablets compressed at compression force of <100 kg/cm² exhibited low hardness with total porosity of 15.39% and significantly increased (P<0.05) metoprolol succinate release as compared to tablets compressed at 2000 kg/cm² with 6.90% of total porosity revealing influence of compression force. Compritol^® 888ATO holds great potential in providing reliable and controlled release profile of highly water soluble metoprolol succinate.     

The Impact of Dose and Solubility of Additives on the Release from HPMC Matrix Tablets—Identifying Critical Conditions

Purpose  The dissolution of HPMC matrix tablets containing different amounts of highly soluble (mannitol) or poorly soluble (dicalcium phosphate, DCP) was studied to deduce the parameters critical to release robustness. Methods  The release of HPMC and additives was studied using a modified USP II method at two paddle stirring rates, 50 and 125 rpm, at HPMC content varying from 15% to 100%. Results  At HPMC contents between 30% and 35% a critical point was identified and found crucial to the release from the HPMC/mannitol tablets. Below this point the matrix rapidly disintegrated in a non robust manner. At higher HPMC contents the mannitol release became increasingly diffusion controlled with maintained matrix integrity. The release robustness was lower for HPMC/DCP than HPMC/mannitol tablets at high HPMC contents, however, lacking critical points. The critical point was interpreted as the percolation threshold for HPMC and differences explained in terms of water transport into the matrix. Conclusion  The release robustness was lower for formulations with additives of low solubility having an erosion controlled release than for additives with higher solubility and a diffusion controlled release. However, for additives creating a steep osmotic pressure gradient, an HPMC content above the percolation threshold becomes vital for maintaining the release robustness.     

Influence of Type and Level of Water-Soluble Additives on Drug Release and Surface and Mechanical Properties of Surelease® Films

Ethylcellulose in combination with water-soluble additives has been used in the development of microporous membrane-coated dosage forms. In the present study, application of three types of water-soluble additives, namely polyethylene glycols (PEG 400, 3350, and 8000), maltodextrins (Maltrin M150, M100, and M040 in the order of lower to higher average polymer size and molecular weight; dextrose equivalence 16.9, 11.1, and 4.8, respectively), and xylitol, as porosity modifiers in the films of a commercially available aqueous ethylcellulose dispersion (Surelease/E-7-7060 plasticized with glyceryl tricaprylate/caprate) was investigated. The effect of type and level of these additives on drug release characteristics and surface and mechanical properties of the polymeric films was studied. Each additive was incorporated at 20 and 30% levels in the polymeric dispersion based on its solids content. Ibuprofen tablets were coated using the polymeric dispersion with and without additive at 3% w/w coat level in a fluid-bed equipment. The coated tablets were evaluated for their drug release rate, coat reflectivity (gloss), Brinell hardness, and elastic modulus. Differential scanning calorimetric analysis of the films was performed to determine the physico-chemical changes in the applied film-coats. The rate of drug release, hence film porosity, was observed to be dependent on the type and level of the additive added. The molecular weight of the additive and its concentration in the polymeric dispersion had significant influence on the rate of drug release, hardness, and elasticity of the film-coats.     

Evaluation of Spironolactone Solid Dispersions Prepared by Co-Spray Drying With Soluplus® and Polyvinylpyrrolidone and Influence of Tableting on Drug Release

Solid dispersions of spironolactone with Soluplus^® and polyvinylpyrrolidone were prepared by spray drying according to a mixture experimental design and evaluated for moisture content, particle size, drug solubility, crystallinity (powder X-ray diffraction and differential scanning calorimetry), and physicochemical interactions (Fourier-transform infrared spectroscopy, Raman). In vitro dissolution was evaluated for the spray dried product itself and after compression into tablets, and prediction models were derived using multiple linear regression analysis. The spray dried products consisted of amorphous drug, indicated by the absence of crystalline powder X-ray diffraction peaks. Amorphization and interactions impacted changes in the Fourier-transform infrared spectroscopy spectra in the ranges 2900-3000 cm^?1 (C-H) and 1600-1800 cm^?1 (C=O) and caused merging at 1690 cm^?1 (C=O of lactone) and 1670 cm^?1 (C=O of thioacetyl group). In the Raman spectra, amorphization and interactions resulted in disappearance of peak at 1690 cm^?1 (C=O) and merging of peaks at 582 and 600 cm^?1 (C-S). Hydrogen bonding between the thioacetyl group of the drug with the hydroxyl groups of Soluplus^® caused marked suppression of the peak at 1190 cm^?1 (R-C(=O)-S vibration). Amorphization and interactions resulted in improved solubility and dissolution which was greatest for drug/Soluplus^® ratio 1:4 and was also demonstrated in the corresponding tablets.     

Drug Release from Ammonio–Methacrylate-Coated Diltiazem Particles: Influence of the Reservoir on Membrane Behavior

Drug-layered sugar spheres 15, 45, and 64% potent were made such that each had the same particle size distribution. The particles were coated to the same coat thickness with an ammonio polymethacrylate formulation, and drug release was measured in two media. The products exhibited a sigmoidal release pattern, where a lag time was followed by relatively rapid drug release. Lag time depended on the applied polymer amount, the media used, and the sugar content, where an increase in sugar content caused greater expansion before drug release. Lag times were related to expansion. Expansion of coated sugar spheres was measured.     

Development of Solid SEDDS,V: Compaction and Drug Release Properties of Tablets Prepared by Adsorbing Lipid-Based Formulations onto Neusilin® US2

Purpose

To develop tablet formulations by adsorbing liquid self-emulsifying drug delivery systems (SEDDS) onto Neusilin®US2, a porous silicate.

Methods

Nine SEDDS were prepared by combining a medium chain monoglyceride, Capmul MCM EP, a medium chain triglyceride, Captex 355 EP/NF, or their mixtures with a surfactant Cremophor EL, and a model drug, probucol, was then dissolved. The solutions were directly adsorbed onto Neusilin®US2 at 1:1 w/w ratio. Content uniformity, bulk and tap density, compressibility index, Hausner ratio and angle of repose of the powders formed were determined. The powders were then compressed into tablets. The dispersion of SEDDS from tablets was studied in 250 mL of 0.01NHCl (USP dissolution apparatus; 50 RPM; 37°C) and compared with that of liquid SEDDS.

Results

After adsorption of liquid SEDDS onto Neusilin®US2, all powders demonstrated acceptable flow properties and content uniformity for development into tablet. Tablets with good tensile strength (>1 MPa) at the compression pressure of 45 to 135 MPa were obtained. Complete drug release from tablets was observed if the SEDDS did not form gels in contact with water; the gel formation clogged pores of the silicate and trapped the liquid inside pores.

Conclusion

Liquid SEDDS were successfully developed into tablets by adsorbing them onto Neusilin®US2. Complete drug release from tablets could be obtained.

     

Influence of plasticizer type and level on the properties of Eudragit® S100 matrix pellets prepared by hot-melt extrusion

Matrix-type pellets with controlled-release properties may be prepared by hot-melt extrusion applying a single-step, continuous process. However, the manufacture of gastric-resistant pellets is challenging due to the high glass transition temperature of most enteric polymers and an unacceptably high, diffusion-controlled drug release from the matrix during the acidic phase. The objective was to investigate the influence of three plasticizers (triethyl citrate, methylparaben and polyethylene glycol 8000) at two levels (10% or 20%) on the properties of hot-melt extruded Eudragit® S100 matrix pellets. Extrusion experiments showed that all plasticizers produced similar reductions in polymer melt viscosity. Differential scanning calorimetry and powder X-ray diffraction demonstrated that the solid state plasticizers were present in the amorphous state. The drug release in acidic medium was influenced by the aqueous solubility of the plasticizer. Less than 10% drug was released after 2 h at pH 1.2 when triethyl citrate or methylparaben was used, independent of the plasticizer level. Drug release at pH 7.4 resulted from polymer dissolution and was not influenced by low levels of plasticizer, but increased significantly at the 20% level. Mechanical testing by diametral compression demonstrated the high tensile strength of the hot-melt extruded pellets that decreased when plasticizers were present.     

Heparin–Paclitaxel Conjugates Using Mixed Anhydride as Intermediate: Synthesis,Influence of Polymer Structure on Drug Release,Anticoagulant Activity and <Emphasis Type="BoldItalic">In Vitro</Emphasis> Efficiency

Purpose  The heparin–paclitaxel conjugates using amino acid as linker (HD2), with low anticoagulant activity, the similar anticancer activity as paclitaxel, offer great potential for further investigation. Methods  Two types of heparin–paclitaxel conjugates (HD) have been developed, in which O-acetylated heparin as carrier conjugates with paclitaxel by direct ester bond (HD1) and by inserting different amino acids as spacers, including valine, leucine, and phenylalanine (HD2a, HD2b, and HD2c), respectively. Specifically, mixed anhydride groups of carrier as activating intermediates mediate the synthesis of prodrugs. The HD conjugates are characterized by ¹H NMR, FT-IR and GPC. The percentage weight of drug and hydrolysis rate for HD are detected by UV and HPLC. The anticoagulant activity and cell cycle of MCF-7 of HD are measured by APTT and FCM, respectively. Results   HD2 conjugates show better solubility and faster hydrolysis rates than those of HD1. Meanwhile, the anticoagulant activity of HD is reduced and FCM analysis show that MCF-7 cells treated with HD are arrested in the G2/M phase of cell cycle. Conclusions  Amino acids as linkers between paclitaxel and carrier are appropriate to facilitate the release of paclitaxel from carrier. Mixed anhydrides mediate the synthesis of prodrugs and HD2 conjugates are expected to further investigate in vivo experiment. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.