Influence of the feed frame design on the powder behavior and the residence time distribution.

The feed frame system is one of the key elements of a rotary tablet press. The powder in the funnel flows through the feed frame system, which ensures a uniform powder flow to the die disc. The objective of the present study was to investigate the effect of different feed frame designs of a production-scale rotary tablet press on the residence time distribution of two microcrystalline cellulose blends, one of them serving as a tracer blend and the other serving as a filling material. With these powder blends, the effect of a reduction of the filling volume of a three chamber feed frame on the powder residence time was investigated. It was shown, that the volume reduction of the three chamber feed frame equipped with three modified large hub wheels led to a decrease of the powder residence time as well as to low intermixing of the powder particles. Furthermore, the residence time distribution within the three chamber feed frame was compared to that within a single chamber cone-shaped feed frame. Both feed frame designs had a similar filling volume but different powder paths through the respective feed frame chambers. The results showed that the single chamber feed frame led to a narrower distribution of the powder residence time and a lower intermixing than the three chamber feed frame. An interesting output of the study was that the variation of the feed frame design had a more pronounced effect on the powder behavior than the variation of the filling volume.

The effect of different feed frame components on the powder behavior and the residence time distribution with regard to the continuous manufacturing of tablets.

The present study focused on the effect of different feed frame components on the residence time distribution of a three-chamber feed frame system (Fill-O-Matic). A production-scale rotary tablet press was used to simulate the industrial manufacture of tablets. The powder residence time distribution was used to characterize the powder behavior in the Fill-O-Matic. Therefore, two powder blends based on microcrystalline cellulose, one of them serving as a plain powder blend (MCC blend) and the other blend (tracer blend) spray colored with an indigo carmine solution by a fluid bed granulator, were used. With these powder blends, the effect of the reduction of the Fill-O-Matic volume with a perspex disc on the residence time distribution was compared with the standard configuration of the Fill-O-Matic. Furthermore, the filling wheel design with regard to the rod shape and different gap size configurations between the feed frame and the die disc were investigated. Interestingly, the reduction of the feed frame volume led to a remarkable decrease of the mean residence time and the mean centered variance. Moreover, the results of the filling wheel design showed that the rod shape of the filling wheels had a high influence on the intermixing of the powder particles in the filling chamber, whereas the corresponding tablet weights and their relative standard deviation were not affected. The gap size between the feed frame and the die disc had low influence on the residence time distribution but an effect on the tablet weights and their standard deviation.

Analysis of the powder behavior and the residence time distribution within a production scale rotary tablet press.

This study focuses on the behavior of powder particles in a rotary tablet press with special focus on the feed frame system. To obtain a better knowledge of the continuous manufacturing of tablets, the experimental setup was carried out with a production scale rotary tablet press. The behavior of the powder particles at different flow rates through the tablet press, residual moisture contents, particle sizes, and amounts of tracer was investigated. The residence time distribution was evaluated using the tracer indigo carmine, which was sprayed onto microcrystalline cellulose particle as solution with fluidized bed spray granulator to obtain a tracer blend. The residence time distribution was increased by increasing the amount of tracer blend, and a transition from a plain MCC blend to the tracer blend with regard to continuous manufacturing was shown. Furthermore, it was found that an increase in the flow rates of the powder particles through the tablet press led to a decrease of the residence time distribution (Et). The variation of the flow rate had no influence on the mechanically applied strain at high throughputs, which was confirmed by a constant number of paddle passes (Npp). At the lowest flow rate, the Npp appears to be higher than the constant Npp values at higher flow rates. The residual moisture content did not shown any significant influence on the residence time distribution. The examination of the effect of different tracer blend particle sizes led to an interesting result: It was shown that the particle size segregation only had a low influence on Et. However, a comparably higher influence of the particle size segregation on the particle distribution in the produced tablets was demonstrated. Large particles were deposited at the top of the tablet surface whereas small particles were deposited at their bottom.

A novel method for determination of the filling level in the feed frame of a rotary tablet press.

AIM: The aim of this study was to investigate whether the filling level within the feed frame of a rotary tablet press can be quantified by laser triangulation combined with the angle recognition of one paddle wheel via rotary encoder. SIGNIFICANCE: Rotary tablet press feed frames are supposed to assure a uniform die filling and, thus, to guarantee the weight and content uniformity of the resulting tablets. Therefore, a constant bulk availability and flow within the feed frame is crucial and has to be ensured by the feed frame design and the operating conditions. So far, there is no instrument available to monitor the bulk filling level or the bulk distribution within feed frames. METHODS: Calcium phosphate dihydrate was used as model powder. The powder surface level was determined via laser triangulation and the angle position of the paddle wheel was monitored via incremental rotary encoder. The data of both parameters was acquired synchronously and evaluated by in-house written software. RESULTS: Different powder masses led to significantly different filling level signals. The experiments showed a high reproducibility of the determined filling levels. Furthermore, an influence of the rotational speed on the powder distribution was observed. CONCLUSIONS: The developed instrument may be used for quantification of the volumetric filling level within rotary tablet press feed frames. It may either be used to better understand the powder behavior within feed frames or for improvement of the die filling process by implementing the device into a feedback loop.

Controlled release of acidic drugs in compendial and physiological hydrogen carbonate buffer from polymer blend-coated oral solid dosage forms.

The objective of this study was to investigate the suitability of "Eudragit® RL/Eudragit® L55" (RL/L55) blend coatings for a pH-independent release of acidic drugs. A coating for ketoprofen and naproxen mini tablets was developed showing constant drug release rate under pharmacopeial two-stage test conditions for at least 300 min. To simulate drug release from the mini tablets coated with RL/L55 blends in the gastrointestinal (GI) tract, drug release profiles in Hanks buffer pH 6.8 were recorded and compared with drug release profiles in compendial media. RL/L55 blend coatings showed increased drug permeability in Hanks buffer pH 6.8 compared to phosphate buffer pH 6.8 due to its higher ion concentration. However, drug release rates of acidic drugs were lower in Hanks buffer pH 6.8 because of the lower buffer capacity resulting in reduced drug solubility. Further dissolution tests were performed in Hanks buffer using pH sequences simulating the physiological pH conditions in the GI tract. Drug release from mini tablets coated with an RL/L55 blend (8:1) was insensitive to pH changes of the medium within the pH range of 5.8-7.5. It was concluded that coatings of RL/L55 blends show a high potential for application in coated oral drug delivery systems with a special focus on pH-independent release of acidic drugs.

Mixture design approach for early stage formulation development of a transdermal delivery system.

Transdermal delivery systems (TDS) consisting of mixtures of adhesives also named multiple polymer adhesive systems are rarely found in the market and research has only been performed on a few of them. Following the principles of ICH Q8, a Design of Experiments (DOE) approach was selected for the formulation development. For evaluation of the statistical method of "mixture design", blends of silicon adhesive, acrylic adhesive, oleyl alcohol as a surfactant and ibuprofen as a model drug were considered to be combined at different concentrations. A randomized design of 16 runs with five replicates and five runs to estimate the lack of fit (LOF) was generated. Samples were tested for adhesion properties, stability of the wet mixes, solubility of the API in the matrix and appearance of the matrix. After performing an ANOVA with the results, response surfaces of tack, shear adhesion, extent of creaming, crystallization behavior, droplet size and droplet size range were derived as contour plots. It could be shown that crystal growth of ibuprofen correlates well with droplet size and droplet size range, where lowest values for crystallization were found with mixtures containing small droplets. However, it was observed that oleyl alcohol showed no positive effect on the miscibility of the polymers and no improvement of the solubility of ibuprofen in the mixtures. With a reasonable number of experiments, the development of a design space for a TDS via mixture design gave valuable information on the product as well as on the interactions of the components.

Coatings from blends of Eudragit® RL and L55: a novel approach in pH-controlled drug release.

The aim of the present study was to investigate the drug release from theophylline pellets coated with blends of quaternary polymethacrylate and methacrylic acid-ethyl acrylate copolymers. Pellets were coated with blends of Eudragit(®) RL PO (RL) and Eudragit(®) L 100-55 (L55) in either organic solution or aqueous dispersion at various copolymer ratios. Generally, the coatings were less permeable for theophylline in phosphate buffer pH 6.8 than they were in hydrochloric acid pH 1.2. Further dissolution experiments revealed that the differences in drug release are caused by the different pH values. A design of experiments for historical data was performed on drug release data of pellets with different coating levels and blend ratios of RL and L55. Drug release in hydrochloric acid was predominantly affected by the coating level, whereas for drug release in phosphate buffer pH 6.8 the blend ratio was the determining factor. As expected, dissolution experiments at different pH values showed that drug release depends on the ratio of dissociated L55 to RL because ionization is a requirement for the functional groups to interact. With the dissolution test for delayed-release solid dosage forms (Ph. Eur.) it was demonstrated that the unique release behavior in neutral media is preserved after the exposition to hydrochloric acid. These findings indicate that the combination of RL and L55 in coatings prepared from solutions is a promising approach for controlled drug release.

Plasticization and antiplasticization of an acrylic pressure sensitive adhesive by ibuprofen and their effect on the adhesion properties.

In transdermal patches, an unpredictable alteration of the mechanical behavior of the pressure sensitive adhesive (PSA) can occur if a drug is added. In the present study, the suitability of Dynamic Mechanical Analysis (DMA)/Dynamic Mechanical Thermal Analysis (DMTA) as methodologies to detect the change in adhesion properties caused by the addition of an API was examined. With DMA/DMTA, time- and temperature-dependent viscoelastic properties were determined. Tack and shear adhesion of blends of the acrylic adhesive DuroTak® 87-4287 and ibuprofen at increasing concentrations were investigated. Interestingly, the probe tack test showed highest values at 1% ibuprofen concentration in the PSA and decreasing values with increasing ibuprofen concentrations. The shear adhesion of the PSA was decreased at all investigated ibuprofen concentrations. With DMA/DMTA, it could be demonstrated that antiplasticization and plasticization are responsible for the change in tack. The main reason for the decrease in shear adhesion is a shift of the Tg to lower temperatures, while antiplasticization only has a marginal effect. The term "antiplasticizing space" was introduced because antiplasticization depends on time, temperature, stress, strain, and API concentration. In general, this antiplasticizing space can have an impact on processing, stability, and in vivo behavior of API/polymer blends in drug formulations.

Tableting properties of silica aerogel and other silicates.

CONTEXT: In solid oral dosage forms silicates are commonly used as glidants in low concentration. However, due to their large specific surface area, silicates may also be used as carrier materials for drugs. Moreover, silicates allow amorphisation of drugs by co-grinding or processing with supercritical fluids. OBJECTIVE: The aim of this study was to investigate the physical and the tableting properties of Silica Aerogel (special type of silica with an extremely large specific surface area), Neusilin(®) US2 (magnesium aluminometasilicate), Florite(®) (calcium silicate) and Aerosil(®) 200 (colloidal silica). MATERIALS AND METHODS: Powder blends of Avicel(®) PH102 (microcrystalline cellulose) and different amounts of the respective silicate were compacted and analyzed for their tabletability (tensile strength vs. compaction pressure) as well as their Heckel plot. RESULTS AND DISCUSSION: With Neusilin(®) the tabletability appeared to be independent of the silicate concentration, whereas with Florite(®) an increasing silicate concentration led to a higher tensile strength. In contrast, the addition of Silica Aerogel and Aerosil(®) resulted in a decrease of the tensile strength. With Aerosil(®) a maximum tolerable concentration of 20% [w/w] was determined. Plastic deformation of all powder blends decreased with increasing silicate concentration. This effect was most pronounced with Aerosil(®) and least with Florite(®). CONCLUSION: Tablets with acceptable tensile strength were obtained with all plain silicates except for Aerosil(®). Therefore, these silicates may be used in tablet formulations, e.g. as carrier materials for liquid or amorphous drugs.

Enhancement of griseofulvin release from liquisolid compacts.

The potential of hydrophilic aerogel formulations and liquisolid systems to improve the release of poorly soluble drugs was investigated using griseofulvin as model drug. The in vitro release rates of this drug formulated as directly compressed tablets containing crystalline griseofulvin were compared to aerogel tablets with the drug adsorbed onto hydrophilic silica aerogel and to liquisolid compacts containing the drug dissolved or suspended in PEG 300. Furthermore, the commonly used carrier and coating materials in liquisolid systems Avicel® and Aerosil® were replaced by Neusilin®, an amorphous magnesium aluminometasilicate with an extremely high specific surface area of 339 m²/g to improve the liquisolid approach. Both the liquisolid compacts containing the drug dissolved in PEG 300 and the aerogel tablets showed a considerably faster drug release than the directly compressed tablets. With liquisolid compacts containing the drug suspended in PEG 300, the release rate increased with rising fraction of dissolved drug in the liquid portion. It could be shown that Neusilin® with its sevenfold higher liquid adsorption capacity than the commonly used Avicel® and Aerosil® allows the production of liquisolid formulations with lower tablet weights.

Comparison of traditional and novel tableting excipients: physical and compaction properties.

CONTEXT: Novel tableting excipients are continuously developed and advertised with superior flow and compaction characteristics. OBJECTIVE: The objective of this study was to compare two traditionally used and two novel tableting excipients with regard to their physical and tableting properties as well as their magnesium stearate sensitivity. Avicel(®) PH102 (microcrystalline cellulose) was compared to the novel co-processed excipient Prosolv(®) SMCC90 (silicified microcrystalline cellulose), whereas Anhydrous Emcompress(®) (anhydrous dicalcium phosphate) was compared to the novel spherically granulated excipient Fujicalin(®) (anhydrous dicalcium phosphate). MATERIALS AND METHODS: True density, particle size, specific surface area (SSA), flowability, tabletability, and magnesium stearate sensitivity of the excipients was determined. RESULTS AND DISCUSSION: Due to the silification process (Prosolv(®)) and the unique manufacturing process (Fujicalin(®)), the novel excipients showed a comparably larger SSA. Hardest tablets by far could be obtained with Prosolv(®), followed by Avicel(®) and Fujicalin(®). Avicel(®) and Prosolv(®) were sensitive to magnesium stearate, whereas Fujicalin(®) and Emcompress(®) did not show lubricant sensitivity. This confirms the plastic deformation behavior of microcrystalline cellulose and the brittle fracture of anhydrous dicalcium phosphate. CONCLUSION: Compared to the traditional excipients the investigated novel tableting excipients were advantageous with regard to their SSA and their tableting properties.

Effects of various vehicles on skin hydration in vivo.

The stratum corneum, the outermost layer of the skin, regulates the passive loss of water to the environment. Furthermore, it is well accepted that drug penetration is influenced by skin hydration, which may be manipulated by the application of moisturizing or oleaginous vehicles. Measurements of transepidermal water loss (TEWL), and of skin hydration using a corneometer, were used to assess the effect of different vehicles on stratum corneum barrier function in vivo in human volunteers. A microemulsion significantly increased skin hydration relative to a reference vehicle based on medium chain triglycerides; in contrast, Transcutol(R) lowered skin hydration. TEWL measurements confirmed these observations.

Pharmacodynamics and dermatopharmacokinetics of betamethasone 17-valerate: assessment of topical bioavailability.

BACKGROUND: The bioavailability of most topically delivered drugs is difficult to quantify, but is generally believed to be very low. With the exception of the vasoconstrictor assay for corticosteroids, no methodology to quantify the rate and extent of drug delivery to the skin has been validated. Recent research has examined the dermatopharmacokinetic (DPK) technique, which is based on stratum corneum (SC) tape-stripping. OBJECTIVE: To compare the in vivo bioavailability of different topical formulations of betamethasone 17-valerate (BMV) using the vasoconstrictor assay and the DPK method. METHODS: BMV was formulated in different vehicles and the drug concentration was adjusted to either (i) equal thermodynamic activity, or (ii) a range of values up to that corresponding to 80% of maximum thermodynamic activity. Vasoconstriction, an accepted and widely used method to determine bioavailability and bioequivalence of topical steroids, was quantified with a chromameter over 24 h post-removal of the formulation. Drug uptake into the SC was assessed by tape-stripping. RESULTS: BMV at the same thermodynamic activity in different vehicles provoked similar skin blanching responses, while DPK profiles distinguished between the formulations. Further, skin blanching responses and drug uptake into the SC clearly depended upon the absolute BMV concentration applied. However, while the saturable nature of the pharmacodynamic response was clear, the tape-stripping method distinguished unequivocally between the different formulations and different concentrations. CONCLUSIONS: The DPK approach offers a reliable metric with which to quantify transfer of drug from the vehicle to the SC, and may be useful for topical bioavailability and bioequivalence determinations.

Time of erythema onset after application of methyl nicotinate ointments as response parameter: influence of penetration kinetics and enhancing agents.

The time of erythema onset may be used as a response parameter for quantification of the cutaneous erythema response induced by methyl nicotinate. The vehicles light mineral oil (LMO; test) and medium chain triglycerides (MCT; standard) were compared with regard to the pharmacodynamic response. Moreover, the influence of penetration enhancers on the time of erythema onset was investigated under zero order penetration kinetics. The enhancers dimethyl sulfoxide, diethylene glycol monoethyl ether and three different glycerides in different concentrations were added to MCT as a standard vehicle. All preparations were applied to the forearms of volunteers under infinite dose conditions at different thermodynamic drug activity levels (0.2-3.2% of the saturation level) and different drug concentrations (0.051-0.816%), respectively. Different penetration kinetics do not influence data of erythema onset, as these data are comparable to those obtained under finite dose conditions (first order penetration kinetics). With regard to the penetration enhancers, a significantly enhanced penetration of methyl nicotinate could be observed only for diethylene glycol monoethyl ether and dimethyl sulfoxide. However, no significant difference between light mineral oil and MCT could be found with regard to penetration enhancement. The time of erythema onset is an easy and efficient parameter for quantification of the pharmacodynamic response caused by nicotinates.

Solid state interactions between the proton pump inhibitor omeprazole and various enteric coating polymers.

The influence of the acidic film formers Eudragit L 100, HPMCAS-HF, HP-55, and shellac on the stability of the acid-labile proton pump inhibitor omeprazole in solid drug-polymer blends at accelerated storage conditions (40 degrees C/75% RH) was determined by fourier transform infrared spectroscopy (FTIR), modulated temperature differential scanning calorimetry (MTDSC), and high performance liquid chromatography (HPLC). As expected, acidic polymers caused a degradation of omeprazole which was manifested by discolorations and increasing amounts of degradation products. However, MTDSC curves and FTIR spectra did not show additional peaks resulting from the omeprazole degradation products. These methods appeared to be not sensitive enough to separate analytically the drug and polymer signals from those of the decomposition products. With HPLC a sufficient quantification of the degradation products was possible. HP-55 caused the highest degree of omeprazole degradation, followed by shellac, HPMCAS-HF, and Eudragit L 100. No correlation with the microenvironmental pH values generated by the acidic polymers at the applied storage conditions was found. The melting process and the dissolution of acidic impurities were figured out as possible reasons for the more pronounced decomposition of the drug in presence of HP-55 and shellac.

Quantification of omeprazole degradation by enteric coating polymers: an UV-VIS spectroscopy study.

The aim of this study was to investigate the degradation of the acid-labile proton-pump-inhibitor omeprazole in organic polymer solutions and aqueous dispersions of enteric coating polymers by UV spectroscopy. Furthermore, data were compared with those obtained in a previous HPLC study. For comparative purposes the cationic Eudragit RS 100 and the monomeric acid acetic acid were included in this study. The discolorations of degraded omeprazole solutions were analysed by VIS spectroscopy. UV-VIS spectra were recorded after preparation of the solutions and after 180 min of storage. The change of absorption was calculated as the difference of the absorption values at 305 nm. Degradation of omeprazole depends on the amount of acidic groups in the polymer structure. This decomposition manifests itself in a shifting of the absorption maximum to lower wavelengths and a decrease of absorption intensity. UV-VIS spectroscopy was used to determine the extent of degradation induced by enteric polymers. A good correlation of these results with previous HPLC data was found when excluding UV absorbing polymers. Nevertheless, values obtained by UV-VIS spectroscopy were always lower than those obtained by HPLC. For evaluation of the discoloration of degraded omeprazole solutions, VIS spectroscopy is a simple and fast method.

Degradation of omeprazole induced by enteric polymer solutions and aqueous dispersions: HPLC investigations.

Two reversed-phase high-performance liquid chromatography (RP-HPLC) methods were developed to investigate the degradation of the acid-labile proton-pump-inhibitor omeprazole in organic polymer solutions and aqueous dispersions of enteric coating polymers (Eudragit L-100, S-100, CAP, HP-55, HPMCAS-HF, -LF, and shellac). The overall goal of the study was to determine the influence of the polymer structure on the degradation of omeprazole, i.e., whether the acid structure of the enteric coating polymers caused an instability of the proton pump inhibitor. Moreover, it was investigated whether a difference in omeprazole degradation could be detected between organic polymer solutions and aqueous dispersions. pKa values of the polymers and pH values of the aqueous dispersions were determined to see whether there was a correlation with the extent of degradation of omeprazole induced by enteric polymers. As the polymers containing phthalate moieties are very susceptible to hydrolysis, the influence of free phthalic acid on omeprazole stability was investigated. Finally, the degradation kinetics of omeprazole in organic polymer solutions were determined. Omeprazole degradation is more pronounced in aqueous polymer dispersions than in organic polymer solutions. The influence of organic polymer solutions on the stability of omeprazole depends on the amount of acidic groups in the polymeric structure, whereas the influence of aqueous polymer dispersions depends on the pH value of the dispersion. The amount of free acids present in some polymers as by-products also cause a degradation of the proton pump inhibitor. Among all investigated polymers, shellac showed the least influence on the stability of omeprazole. The decomposition of omeprazole in organic polymer solutions followed first-order kinetics. The decrease of omeprazole peak area in organic polymer solutions was in the order Eudragit L-100> HPMCAS-HF>shellac.

Effect of cutaneously applied nonionic surfactants and local anesthetic bases on thermal sensations.

With cutaneously applied local anesthetic bases various effects may be observed, such as a decrease in pricking pain and a change in burning, itch, and thermal sensations. These effects occur after skin penetration and may be attributed to the action of the anesthetics on nociceptors and thermoreceptors, i.e., on C and A delta nerve fibers, respectively. As little is known about the pharmacodynamic response of nonionic surfactants with a potentially anesthetic action such as polidocanol, this study characterizes nonionic surfactants pharmacodynamically by measuring thermal thresholds with a thermal sensory analyzer after cutaneous application. The results obtained with the nonionic surfactants were compared with data resulting from the cutaneous application of local anesthetic bases such as mepivacaine, bupivacaine, prilocaine, lidocaine, the 1:1 mixture of lidocaine and prilocaine contained in EMLA and a triple mixture consisting of lidocaine, prilocaine and tetracaine (1:1:1). The results show that none of the investigated surfactants affect thermal thresholds probably due to their high molecular weight. The same was observed with the anesthetics mepivacaine and bupivacaine. In contrast, prilocaine, lidocaine, the 1:1 mixture of lidocaine and prilocaine and the triple mixture consisting of lidocaine, prilocaine and tetracaine (1:1:1) proved to be potent local anesthetics. However, their pharmacodynamic responses do not differ significantly from each other.

Basic coating polymers for the colon-specific drug delivery in inflammatory bowel disease.

During acute attacks of inflammatory bowel disease, the luminal pH of the colon decreases significantly. This drop in pH can be exploited by developing coated dosage forms with acid-soluble coating polymers to achieve topical drug delivery to the colon. Two batches of minitablets, a conventional and a swellable formulation, were prepared by direct compression and coated with different amounts of either Eudragit E or AEA in a small coating pan. The release of the model drug dexamethasone from the coated tablets was measured spectrophotometrically at pH 2.0, 4.0, 5.0, and 6.8 and different stirring rates (100-200 rpm) to simulate the influence of pH and hydrodynamic stress on drug release. In general, lag times of drug release, determined as the time points of a 5% drug release, were longer with AEA-coated cores compared to those coated with Eudragit E, resulting from a lower polymer dissolution rate and water permeability of this film. In low pH media, drug release was dependent on the stirring rate because the onset of drug release is determined by the time required for dissolution of the basic polymer films. At pH 6.8, lag times from nonswelling tablets coated with Eudragit E, for which drug release only begins after complete erosion of the polymer film, are not significantly affected by hydrodynamic stress. Drug release from AEA-coated cores is determined by the slow drug diffusion through the polymer film. Lag times from tablets with swelling properties, for which drug release is induced by disruption of the basic polymer films due to water penetration and subsequent core swelling, are not significantly affected by hydrodynamic stress. Additional coating layers such as an intermediate hydroxypropylcellulose (HPC) layer and an enteric outer layer do not influence the lag times of drug release, nor does a 2-hr pretreatment of the entire dosage form in acidic media.