USP Paddle Method Research Articles

Enhancement of the dissolution of indomethacin in interactive mixtures using added fine lactose

The objective of the study was to investigate the effect of fine lactose on the in vitro dissolution of indomethacin in interactive mixtures containing spray-dried lactose and lactose monohydrate (106–250 μm). Dissolution of the indomethacin was measured using an automated dissolution apparatus following the USP paddle method at 100 rpm. The particle size distributions of indomethacin mixtures were measured using a Mastersizer S under non-sink conditions. Data fitted bi-exponential or tri-exponential dissolution models, representing dissolution from dispersed and agglomerated particle distributions. The addition of fine lactose (VMD 3.8 ± 0.4 μm) to 20% indomethacin-coarse lactose mixtures resulted in significantly increased rates of dissolution caused by increases in the estimated dissolution rate constants for dispersed particles ( K d) and by de-agglomeration. Agglomerates in the mixture showed little tendency to comminute under shear pressure. De-agglomeration in the dissolution medium was attributed to increased porosity of agglomerates, caused by dissolution of water soluble fine lactose in the agglomerate structure. The median particle size ( D 50) of the dispersed particle distribution decreased with increasing concentrations of added fine lactose, indicating increasing extents of de-agglomeration, and a good correlation between K d and ( D 50) 2 resulted for the coarse lactose-based mixtures ( R 2 > 0.984).

Modulation of a Pulsatile Release Drug Delivery System Using Different Swellable/Rupturable Materials

Diclofenac sodium tablets consisting of core coated with two layers of swelling and rupturable coatings were prepared and evaluated as a pulsatile drug delivery system. Cores containing the drug were prepared by direct compression using microcrystalline cellulose and Ludipress as hydrophilic excipients with the ratio of 1:1. Cores were then coated sequentially with an inner swelling layer of different swellable materials; either Explotab, Croscarmellose sodium, or Starch RX 1500, and an outer rupturable layer of different levels of ethylcellulose. The effect of the nature of the swelling layer and the level of the rupturable coating on the lag time and the water uptake were investigated. Drug release rate studies were performed using USP paddle method. Results showed the dependence of the lag time and water uptake prior to tablet rupture on the nature of the swelling layer and the coating levels. Explotab showed a significant decrease in the lag time, followed by Croscarmellose sodium and finally by Starch RX 1500. Increasing the level of ethylcellulose coating retarded the diffusion of the release medium to the swelling layer and the rupture of the coat, thus prolonging the lag time.

Enhancement of dissolution profile by solid dispersion (kneading) technique

This article investigates enhancement of the dissolution profile of valdecoxib using solid dispersion with PVP. The article also describes the preparation of fast-dissolving tablets of valdecoxib by using a high amount of superdisintegrants. A phase solubility method was used to evaluate the effect of various water-soluble polymers on aqueous solubility of valdecoxib. Polyvinyl pyrrolidone (PVP K-30) was selected and solid dispersions were prepared by the method of kneading. Dissolution studies using the USP paddle method were performed for solid dispersions of valdecoxib. Infrared (IR) spectroscopy, differential scanning calorimetry (DSC), and x-ray diffractometry (XRD) were performed to identify the physicochemical interaction between drug and carrier, hence its effect on dissolution. Tablets were formulated containing solid dispersion products and compared with commercial products. IR spectroscopy, XRD, and DSC showed no change in the crystal structure of valdecoxib. Dissolution of valdecoxib improved significantly in solid dispersion products (< 85% in 5 minutes). Tablets containing solid dispersion exhibited better dissolution profile than commercial tablets. Thus, the solid dispersion technique can be successfully used for improvement of dissolution of valdecoxib.

Catanionic mixtures involving a drug: A rather general concept that can be utilized for prolonged drug release from gels

The aim of this work was to study at what extent mixtures of drug substances and oppositely charged surfactants form catanionic aggregates and to apply these as a means of obtaining prolonged drug release from a gel. The properties of traditional catanionic mixtures are relatively well known, but only recently we found that not only traditional surfactants form these mixtures, but also structurally more complex surface active drug compounds. In this study, several different compositions of catanionic mixtures were studied visually, by cryogenic transmission electron microscopy (cryo-TEM) and rheologically using a Bohlin VOR Rheometer. Some of the catanionic vesicle and micelle phases were incorporated in and released from gels using the USP paddle method. The drug compounds investigated were lidocaine, ibuprofen, naproxen, alprenolol, propranolol, and orphenadrine. Of the six drug molecules used in this study, five, both positively and negatively charged, were capable of forming catanionic vesicles and/or micelles with oppositely charged surfactants. The drug release studies show that catanionic drug surfactant mixtures are beneficial for obtaining prolonged release from gels, as the drug release using catanionic vesicles and micelles was prolonged between 10 and 100 times compared to the release of pure drug substance from the gel.

Physicochemical Characterization and Dissolution Properties of CS-891 with Different Crystallinity

Ground CS-891 (N-[1-(4-methoxyphenyl)-1-methylethyl]-3-oxo-4-aza-5a-androst-1-ene--carboxamide) of poorly water soluble drug was obtained using a Heiko Seisakusho model TI-100 vibration mill, and samples with different crystallinity were prepared at mixture ratios of 10:0, 7:3, 5:5, 3:7 and 0:10 (intact;ground CS-891). Physicochemical characterizations were obtained using qualitative and quantitative X-ray diffractometry, different scanning calorimetry (DSC), scanning electron microscopy (SEM), Quantasorb surface area analyzer, and controlled atmosphere microbalance. With increase of amorphous CS-891 in mixture ratios, the intensities of X-ray diffraction peaks of crystalline CS-891 were decreased, whereas surface area, water absorption, and exothermic peaks in DSC were increased. The apparent solubility of ground CS-891 was and the solubility of intact CS-891 was at . The apparent precipitation rates of CS-891 in a supersaturated solution during the solubility test were increased with an increase of amorphous CS-891, and a crystalline form of CS-891 transformed from amorphous CS-891 after the solubility test was found by X-ray diffraction analysis, DSC and SEM. The dissolution profiles of CS-891 with different crystallinity at by the USP paddle method were investigated, and the apparent dissolution rate constant of ground CS-891 was about 5.9-fold higher than that of intact CS-891. A linear relationships between the crystallinity of CS-891 and the apparent dissolution rate constant (r>0.96) were obtained.

Understanding agglomeration of indomethacin during the dissolution of micronised indomethacin mixtures through dissolution and de-agglomeration modeling approaches

The purpose of this research was to correlate the state of agglomeration determined by the modeling of dissolution and de-agglomeration profiles, using mixtures of micronised indomethacin designed to have different dissolution rates and extents of particle agglomeration in dissolution media. Dissolution profiles were determined using the USP paddle method. De-agglomeration profiles were obtained from laser diffraction particle sizing of mixtures of indomethacin in dissolution media under non-sink conditions. Data were modeled and key parameters estimated using a non-linear least squares estimation algorithm. The key parameters of initial apparent volume concentrations as dispersed and agglomerated particles, and dissolution rate constants (for dissolution modeling), and the apparent volume concentrations of dispersible and non-dispersible agglomerates and the de-agglomeration rate constant (for de-agglomeration modeling) were related to indomethacin and sodium lauryl sulphate concentrations in the lactose–povidone mixtures. Micronised sodium lauryl sulphate added to the mixture was more effective in de-agglomeration than equivalent concentrations in the dissolution media. An excellent correlation existed between the total initial apparent volume concentration of agglomerates determined by dissolution and de-agglomeration ( P=0.98). The use of key parameters estimated from the modeling of dissolution and de-agglomeration profiles provides a useful tool in dosage form development of formulations of poorly water soluble drugs.

Comparative Study on Co-Ground Products of Rofecoxib with -Cyclodextrin and Its Sulfobutyl Ether-7 Derivative in Solution and in the Solid State

The inclusion behavior of sulfobutyl ether-7 derivative ofβ-cyclodextrin (SBE7βCD), in solution and solidstate was compared with that of natural β-cyclodextrin(βCD) toward a poorly water-soluble anti-inflammatoryagent, rofecoxib (ROFX), chemically 4[4-(methylsulfonyl)phenyl]-3-phenyl-2 (5H)-furazone. Drug-cyclodextrin solidsystems were prepared by cogrinding in a ball mill. A phasesolubility method was used to evaluate the stoichiometries andstability constants of ROFX-βCD (1 : 1 and 62 M-1)and ROFX-SBE7βCD (1 : 1 and 132 M-1) complexes.The formation of inclusion complexes with βCD andSBE7βCD in the solid state were confirmed by infraredspectroscopy, differential scanning calorimetry, X-ray diffractometry,scanning electron microscopy and in the liquid state by phasesolubility analysis, nuclear magnetic resonance spectroscopy andcircular dichroism studies. Dissolution studies using the USP paddlemethod were carried out in phosphate buffer pH 7.2 at 37 °Cfor both βCD and SBE7βCD complexes of rofecoxib.Solubility enhancement was much greater for the rofecoxib-SBE7βCDcomplex compared to drug-βCD complex. The stability constantobtained for the SBE7βCD inclusion complex of rofecoxib wasthe highest. Finally, dissolution profiles obtained suggest thatSBE7βCD is more effective than β-cyclodextrin inimproving the pharmaceutical properties of rofecoxib.

Release behavior and photo-image of nifedipine tablet coated with high viscosity grade hydroxypropylmethylcellulose: effect of coating conditions

An orally applicable nifedipine-loaded core tablets was coated using high viscosity grade HPMC (100,000 cps) in ethanol/water cosolvent. The release of coated tablet was evaluated using USP paddle method in 900 ml of simulated gastric fluid (pH 1.2) for 2 h followed by intestinal fluid (pH 6.8) for 10 h. The surface morphologies using scanning electron microscope and photo-images using digital camera of coated tablet during the release test were also visualized, respectively. The viscosity of hydro-alcoholic HPMC solution largely decreased as the amount of ethanol increased. There was no significant difference in viscosity among plasticizers used. The distinct and continuous coated layer was observed using scanning electron microscope. However, the surface morphologies were highly dependent on HPMC concentration and ratio of coating solvents. The higher ratio of ethanol/water gave a longer lag time prior to drug release. Lag time also increased as a function of the coating levels based on weight gains due to increased thickness of coated layer. Lag time is inversely correlated with HPMC concentration in ethanol/water (5:1) cosolvent. As the HPMC concentration slightly decreased from 3.8 to 3.2% in hydroalcoholic coating solution, a large increase of lag time was observed. As the swelling (mixing) time of high viscosity grade HPMC in ethanol/water cosolvent increased from 1 to 5 h, the release rate was decreased due to enough plasticization of polymer. Based on photo-imaging analysis, the coated tablet was initially swelled and gelled without erosion and disintegration over 5 h. The disintegration of the coated tablet was occurred approximately 7 h after dissolution, resulting in pulsed release of drug. The high viscosity grade HPMC can be applicable for polymeric coating after careful selection of solvent systems. The release behavior and lag time could be controlled by coating conditions such as HPMC concentration, ethanol/water ratio as a coating solvent, coating level and swelling (mixing) time of coating solution. The current time-controlled release tablet coated with high viscosity grade HPMC with a designated lag time followed by a rapid release may provide an alternative to site specific or colonic delivery of drugs. In addition, the release behavior can be matched with body’s circadian rhythm pattern in chronotherapy.

Effect of sodium lauryl sulfate in dissolution media on dissolution of hard gelatin capsule shells.

Sodium lauryl sulfate (SLS) is a commonly used surfactant in dissolution media for poorly water soluble drugs. However, it has occasionally been observed that SLS negatively impacts the dissolution of drug products formulated in gelatin capsules. This study investigated the effect of SLS on the dissolution of hard gelatin capsule shells. The USP paddle method was used with online UV monitoring at 214 nm (peptide bond). Empty size #0 capsule shells were held to the bottom of the dissolution vessel by magnetic three-prong sinkers. SLS significantly slowed down the dissolution of gelatin shells at pH < 5. Visually, the gelatin shells transformed into some less-soluble precipitate under these conditions. This precipitate was found to contain a higher sulfur content than the gelatin control sample by elemental analysis, indicating that SLS is part of the precipitate. Additionally, the slowdown of capsule shell dissolution was shown to be dependent on the SLS concentration and the ionic strength of the media. SLS interacts with gelatin to form a less-soluble precipitate at pH < 5. The use of SLS in dissolution media at acidic pH should be carefully evaluated for gelatin capsule products.

Characterization of Ibuproxam Binary and Ternary Dispersions with Hydrophilic Carriers

This work investigates the possibility of increasing the dissolution properties of ibuproxam (a poorly water‐soluble anti‐inflammatory drug) using hydrophilic carriers such as polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), or urea, alone or in combination. Phase‐solubility studies showed that the carrier solubilizing power was in the order PEG > PVP > urea and evidenced a synergistic effect in drug solubility improvement when using carrier combinations. Binary and ternary systems, at 20/80 or 20/40/40 (w/w) drug/carrier(s) ratios, prepared by coevaporation of their ethanolic solutions or by cogrinding physical mixtures in a high‐energy vibrational micromill, were characterized by differential scanning calorimetry (DSC), hot stage microscopy (HSM), and scanning electron microscopy (SEM) analyses. The results of dissolution tests (USP paddle method), in terms of Dissolution Efficiency, indicated that ternary systems were up to 35% more effective than the corresponding binary preparations and coevaporated products were up to 45% more efficacious than the corresponding coground ones. The IBUX‐PEG‐PVP coevaporated was the best product, allowing a more than three‐times increase in Dissolution Efficiency with respect to drug alone; moreover, t50% ( > 60 min for pure ibuproxam) was < 10 min, and 90% dissolution was achieved after 30 min, whereas only 40% was obtained after 60 min for pure drug. The best performance of this system was attributed to a joined effect of the strong amorphizing power of PVP (as demonstrated by solid state analyses) with the high solubilizing efficacy of PEG (as emerged from phase‐solubility studies). The drug dissolution rate from solid dispersions remained practically unchanged after one‐year storage at room temperature in closed containers.

In vitro release of sodium diclofenac from a central core matrix tablet aimed for colonic drug delivery

The present study was aimed at developing a novel sodium diclofenac formulation for colonic release. The proposed delivery system consisted in a polymeric matrix tablet containing a drug central core purposely designed for obtaining a time-controlled release profile characterized by an initial phase of lag-time followed by a controlled release phase, according to zero order kinetics. The spheric central core was formed by a solid dispersion of the drug into the hydrophilic polymer PEG 4000, which enabled an improvement of drug dissolution properties with respect to other carriers such as lactose. Eudragit RS100 was used as inert polymeric matrix for the core coating, mixed (50:50, w/w) with sodium chloride and Emdex as channeling agents. Tablets containing the drug central core were prepared by direct compression, without any other excipient, and tested for dissolution properties according to the USP paddle method, under pH-gradient conditions. For both series of formulations, lag times increased with decreasing the channeling agent particle size, as a consequence of the smaller pores formed by its dissolution. However, formulations containing sodium chloride always showed longer lag times than the corresponding with Emdex and were more effective in providing prolonged zero-order release periods. This was mainly attributed to the plastic deformation properties under compression shown by sodium chloride, leading to a less porous, more compact network which more strictly controlled solvent penetration and drug dissolution and release rates. By varying the sodium chloride/Eudragit w/w ratio, it was possible to suitably modulate the length of both the lag time (for achieving colonic targeting) and zero-order release phases.

Applications of a new device (spindle) for improved characterization of drug release (dissolution) of pharmaceutical products.

A crescent spindle (patent pending) is described which may be used in place of the USP paddle component in USP dissolution apparatus 2. The new spindle is curve shaped, corresponding to the bottom of a dissolution vessel, with attached bristles to fill in the gap between the spindle and the surface of the vessel. The geometry of the new spindle provides more efficient mixing than the USP paddle and prevents accumulation of disintegrated material (no cone formation). Using the new spindle, in comparison with the USP paddle, dissolution characteristics of three drug products: 250 mg amoxicillin capsules, 15.6 g acetylsalicylic acid (ASA) boluses and 200 mg carbamzepine tablets were evaluated. The experimental conditions for dissolution testing with the two stirring devices included; 900 ml of 0.05 M phosphate buffer, pH 6.8 with 50 rpm, 900 ml of 0.05 M acetate buffer, pH 4.5-ethanol (7:3) with 50 rpm, and water containing 1% sodium lauryl sulphate with 75 rpm for amoxicillin capsules, ASA boluses and carbamazepine tablets, respectively. Uncharacteristic of the test products, which are fast release, the USP paddle provides significantly slower drug release. For example, 90 min for <80% drug release vs. 10 min for >90% for amoxicillin capsules and 6 h for 80% vs. 30 min for >90% for ASA boluses with USP paddle vs. the new spindle. In case of the carbamazepine tablets, three products which are bioequivalent and prescribed interchangeably, the USP paddle method shows significantly different dissolution characteristics. However, with the new device, all these products show similar drug release characteristics, a better reflection of product release characteristics and in vivo drug release behaviour. Compared with the USP paddle, the suggested device (spindle) provides improved stirring and mixing which appears to provide more appropriate (biorelevant) characterization of pharmaceutical products.

Dissolution and assaying of multicomponent tablets by chemometric methods using computer-aided spectrophotometer

Dissolution of three component tablets containing paracetamol (APAP), propyphenazone (PP), and caffeine (CAF) was carried out by USP paddle method. Three chemometric methods; inverse least square (ILS), principal component regression (PCR) and partial least squares (PLS) were applied to simultaneous assay of APAP, PP and CAF in tablets. The PCR, PLS and ILS methods were applied to simultaneous dissolution APAP, PP and CAF in tablets using a double beam UV–Vis spectrophotometer without any chemical separation and any graphical treatment of the overlapping spectra of three drugs. Twentytwo mixture solutions in different concentrations were prepared in simulated gastric juice (SGJ, USP) for the chemometric calibrations as training set. The absorbance data matrix was obtained by measuring the absorbance at 14 wavelength points (from 222.5 to 292.5 nm) with the intervals of 5 nm (Δ λ=5 nm) in the spectral region between 200 and 310 nm. Training set and absorbance data were used for the calibrations of chemometric methods. The developed calibrations were tested for the previously prepared solutions of mixture of three drugs for the validation of the assay method. The chemometric calculations were performed by using the ‘ maple v’ software. The results of three chemometric methods were statistically compared with each other. These chemometric calibrations were successfully applied to the content uniformity and dissolution of the multicomponent tablets without any separation procedure. The synthetic mixtures of three drugs were used for the validity of the calibrations. Means recoveries (percent) and relative standard deviation of PLS, PCR and ILS methods were found to be 100.1±0.6, 101.4±1.6 and 100.1±0.6 for APAP; 100.9±3.2, 102.0±3.3 and 100.9±3.2 for PP; 99.9±3.5, 101.6±3.3 and 99.9±3.2 for CAF, respectively. Dissolution profiles of three component tablets were performed. More than 95% of drugs were dissolved within 15 min. All of the three-chemometric methods in this study can be satisfactorily used for the quantitative analysis and for dissolutions test of multicomponent dosage form.

The Effects of Formulation Factors on the Moist Granulation Technique for Controlled-Release Tablets

Controlled-release tablets were prepared by the moist granulation technique (MGT), a granulating method that uses very limited amounts of liquid and requires microcrystalline cellulose (MCC) to absorb moisture. Acetaminophen (APAP) was the model drug, and the polymer hydroxypropylcellulose (HPC) served as the controlled-release agent. The effects of varying drug, binder (polyvinylpyrrolidone, PVP), polymer, and MCC levels on granule properties and tablet dissolution were studied. Dissolution testing was carried out in distilled water using the USP paddle method. In all cases, the granules flowed and compressed well. The granule properties were evaluated by calculating the mean particle size for all batches from sieve analysis data. The results indicate that MGT can be applied to control drug release, and at a polymer content of 44.6% or more, the process is robust enough to allow slight variations in formulation factors without affecting drug release.

Molecular Properties of Propranolol Hydrochloride Prepared as Drug-Resin Complexes

Drug-resin complexes, as well as physical dispersions, containing varying contents of propranolol were prepared. The molecular properties of samples were investigated by differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and infrared (IR) spectroscopy. In addition, the USP paddle method was used to determine the release behavior of drug from various formulations prepared from the samples. The data from DSC and XRPD indicated that the molecular state of drug in the complexes was amorphous, whereas that in the physical dispersions exhibited the crystalline state of pure drug. These results suggested that the molecule of drug prepared as drug-resin complexes was monomolecularly dispersed in the resin bead. The IR study provided evidence that demonstrated the interaction between the drug and resin in the complexes. The release behavior of drug from the complexes was governed by the cross-linkage structure and equilibrium treatment of drug exchange of resin.

Improvement in solubility and dissolution rate of 1,2‐dithiole‐3‐thiones upon complexation with β‐cyclodextrin and its hydroxypropyl and sulfobutyl ether‐7 derivatives

Inclusion complexes between β‐cyclodextrin derivatives and 1,2‐dithione‐3‐thiones were studied in aqueous solution and in the solid state. Phase solubility study was used to evaluate the complexation in solution, at 37 °C, of three cyclodextrins, i.e., β‐cyclodextrin (βCD), hydroxypropyl‐β‐cyclodextrin (HPβCD), sulfobutyl ether‐7‐β‐cyclodextrin (SBE7βCD), and four 1,2‐dithiole‐3‐thiones, i.e., the parent compound dithiolethione (DTT), dimethyldithiolethione (DMDTT), 5‐phenyldithiolethione (5PDTT), and anetholetrithione (ATT). Stability constants of the DTT complexes with HPβCD and SBE7βCD were also determined spectrophotometrically using a nonlinear least‐squares methodology. Differential scanning calorimetry (DSC) and scanning electronic microscopy (SEM) were used to characterize spray‐dried complexes formed between 5PDTT and SBE7βCD, ATT and SBE7βCD. Dissolution studies using the USP paddle method were carried out in water at 37 °C for both ATT and 5PDTT binary systems with HPβCD and SBE7βCD. Solubility enhancements were much greater with the more lipophilic ATT and 5PDTT compared to DTT and DMDTT, whatever the cyclodextrin used, in the rank order SBE7βCD > HPβCD ≫ βCD. Stability constants obtained (between 120 and 12800 mol−1) were also the highest for the more lipophilic drugs and in the same rank order SBE7βCD > HPβCD ≫ βCD. Results obtained by UV spectrophotometry were in good agreement with those obtained by phase‐solubility study. DSC thermograms of spray‐dried complexes of ATT and 5PDTT with HPβCD and SBE7βCD lacked the endothermal peak of pure drug peak which was found for the physical mixtures (107 °C and 125 °C for ATT and 5PDTT, respectively). Finally, dissolution profiles of spray‐dried inclusion complexes studied displayed a faster dissolution rate compared to physical mixtures and pure drugs. The present study showed that complexation of 1,2‐dithiole‐3‐thiones with β‐cyclodextrin derivatives resulted in an increase in solubility, allowing intravenous formulation for bioavailability and metabolism studies and an increase in the dissolution rate of the drugs, which shoud be of interest for oral absorption of these lipophilic compounds.

Modulation of rifampicin release from spray-dried microspheres using combinations of poly-(DL-lactide)

Microspheres containing 20% w/w rifampicin (RIF) with smooth morphology have been readily prepared from combinations of low, R104 (Mw, 2000) and moderate, R202H (Mw, 9000), molecular weight poly(D,L-lactide) (PDLLA) as a means to modulate drug release from either polymer when used alone. These have been characterized with respect to their drug loading, granulometry, in vitro drug release and thermal behaviour. Particle size distributions were Gaussian, whereby mean microsphere diameter was found to increase from 2.11 to 2.98mum as the proportion of more viscous R202H increased, whilst >95% of particles were <10mum, irrespective of the polymer blend used. Use of a reduced inlet temperature for spray-drying gave uncharacteristically high production yields in the range of 55.8-80.7% for the process. Encapsulation efficiencies were quantitative with the weight proportion of drug co-dissolved (p < 0.05), yielding microspheres of high and predictable RIF loading. In vitro drug release revealed a dramatic shift in release profile between 40 and 60% R104. Closer examination in this range showed the predicted pattern of increased release rate as the fraction of more hydrophilic R104 increased. However, disproportionate differences were evident between 44 and 48% R104. From the apparent temperature dependent drug release, the criticality of matrix composition was attributed to the coincidence of matrix softening with the dissolution medium temperature and consequent hydration, which, at a finite composition, resulted in a controlled auto-hydration mechanism. Dramatic dependence of release rate with dissolution methodology was accountable to the fact that drug release was considerably quicker where microspheres remained suspended and individualized with the USP paddle method as opposed to aggregated with the shaking bath methodology. In conclusion, the utility of blending racemic PDLLA to modulate drug release and the convenience of spray-drying as a technique to produce microspheres of predictable character have been demonstrated. The temperature-dependent release exhibited may have application in the site-specific delivery of drugs where local increased biochemical activity promotes drug release in response to an increased pharmacological need.

Matrix Tablets of Carrageenans. II. Release Behavior And Effect of Added Cations

Carrageenans are hydrocolloids in the rubbery state at standard conditions. They are useful excipients for controlled-release tablets. Three carrageenans, two κ-carrageenans (Gelcarin® GP-812 NF and GP-911 NF) and one ι-carrageenan (Gelcarin GP-379 NF), are analyzed regarding their release behavior in combination with sorption, swelling, and rheology. The l-carrageenan has a higher substitution by sulfate groups. The κ-carrageenan Gelcarin GP-812 NF contains a small amount of potassium chloride left over from processing. Water sorption of the pure materials was studied gravimetrically, and the rheology of different solutions (2% and 5% w/w) was studied by cup-cylinder rotation viscosimetry. Swelling was determined as the vertical expansion of the tablets with a specially designed swelling apparatus. Drug release from the tablets was performed by the USP paddle method for 8 hr. The data indicate that drug release increases when water sorption and swelling extent decrease and as viscosity increases. The order of release is nearly zero-order kinetics for theophylline monohydrate, a nonionic drug. Diffusion of the anionic drug diclofenac sodium is anomalous. In addition, the influence of the added salts potassium and calcium chloride on swelling and release was studied. Before tableting, physical mixtures of these salts with and without theophylline monohydrate were prepared. Swelling and release change in the same order, but this is only valid when the ionic interactions responsible for this are strong enough. Besides this, physical mixing of salts with the carrageenans can result in an increased release of drug caused by decreased cohesion of the matrix during drug release, mainly for calcium chloride.

Alternative Solvent-Free Preparation Methods for Felodipine Surface Solid Dispersions

Surface solid dispersions were prepared via physical mixture and were either heated in a vacuum dryer or in a microwave oven for different periods of time. The physical state of felodipine in solid dispersions was studied using differential scanning calorimetry and x-ray powder diffractometry. USP paddle method was used for felodipine dissolution studies. The use of vacuum or microwave energy led to a significant improvement of felodipine dissolution which was caused partly by the amorphous state of felodipine and a large surface area of amorphous silicon dioxide.

The Release Mechanism of an Oral Controlled-Release Delivery System for Indomethacin

ABSTRACTThis study was carried out to fully characterize the release kinetics of an oral controlled-release tablet formulation of indomethacin with xanthan gum. Matrix swelling, matrix erosion, and drug diffusion studies were performed to elucidate the operative release mechanisms of a tablet compressed from a ternary mixture of indomethacin-xanthan gum-lactose. Drug release tests were performed according to the USP paddle method in phosphate buffer pH 7.4, concurrently with the dissolution of the gum. Mean dissolution time (MDT) of the drug was calculated from the release profile and it was used as a parameter to evaluate the influence of (a) polymer content in the dosage form, (b) ionic strength of the medium, and (c) the rotation speed of the paddle on the release characteristics of the drug. There is a linear relationship between MDT and the inverse of polymer content. Within the range of ionic strength of the gastrointestinal tract, the salt concentration of the dissolution medium has a negative (inhibitory) effect on release rate of the drug and on matrix swelling. A positive (enhancing) influence of the salt concentration on drug diffusion in the hydrated matrices was noted. The polymer dissolution follows almost immediately the dissolution of the drug. A linear relationship between MDT and the inverse of paddle rotation speed has been observed. Swelling-controlled erosional process is the operative mechanism for indomethacin release from xanthan gum matrices.