The purpose of present study was to evaluate commercial preparations of carbamazepine tablets with respect to drug release through a defined sequence of experiments using Minitab software. The compliance of products with respect to United States Pharmacopeia (USP) dissolution test and comparison of the products with respect to drug release in different dissolution conditions is reported in the present paper. The different dissolution conditions studied include dissolution medium (1% SLS in purified water, 0.1 N HCl), volume (900 and 1,000 ml), rpm (50 rpm, 75 rpm). Studies indicated that all six products complied with USP dissolution criteria. However, the extent of influence of dissolution conditions on drug release was varied among the products. Distinct dissolution profiles were observed and there was no correlation with disintegration time in certain products. The in vitro dissolution experimentation helped in identifying the discriminatory dissolution conditions and also the formulations that were unaffected with change of dissolution variables. In summary, commercial preparations of carbamazepine vary widely in their dissolution behavior in multi dissolution run experimentation. Identifying this behavior of the products was essential as an in vitro tool for screening a good and a bad formulation.
carbamazepine; dissolution; drug release; sodium lauryl sulfate
In the sublingual (SL) cavity, compared with the gastrointestinal tract, tablets are subjected to minimal physiological agitation, and a limited volume of saliva is available to facilitate disintegration and dissolution. None of the official compendial dissolution apparatuses and methods simulate these SL conditions. In this study, a custom-made dissolution apparatus was constructed, and a novel in vitro method that simulates SL conditions was evaluated. Several epinephrine 40 mg SL tablet formulations under development and two commercial SL tablets, isosorbide dinitrate 5 mg and nitroglycerin 0.6 mg, were studied. The dissolution medium was 2 mL of distilled water at 25°C. Dissolution was measured at 60 and 120 s. The novel in vitro method was validated for accuracy, reproducibility, and discrimination capability, and was compared with the official US Pharmacopeia (USP) dissolution method using apparatus 2 (Paddle). The data obtained following the novel in vitro method were accurate and reproducible. This method was capable of detecting minor changes in SL formulations that could not be detected using other in vitro tests. Results from the official USP dissolution method and our novel in vitro method were significantly different (p < 0.05). Results reflecting the dissolution of rapidly disintegrating tablets using simulated SL conditions were obtained using the novel in vitro dissolution method.
custom-made dissolution apparatus; development and validation; dissolution testing; novel in vitro dissolution method; sublingual tablets
The purpose of the work was to investigate correlation between disintegration and dissolution for immediate release tablets containing a high solubility drug and to identify formulations where disintegration test, instead of the dissolution test, may be used as the acceptance criteria based on International Conference on Harmonization Q6A guidelines. A statistical design of experiments was used to study the effect of filler, binder, disintegrating agent, and tablet hardness on the disintegration and dissolution of verapamil hydrochloride tablets. All formulation variables, i.e., filler, binder, and disintegrating agent, were found to influence tablet dissolution and disintegration, with the filler and disintegrating agent exerting the most significant influence. Slower dissolution was observed with increasing disintegration time when either the filler or the disintegrating agent was kept constant. However, no direct corelationship was observed between the disintegration and dissolution across all formulations due to the interactions between different formulation components. Although all tablets containing sodium carboxymethyl cellulose as the disintegrating agent, disintegrated in less than 3 min, half of them failed to meet the US Pharmacopeia 30 dissolution criteria for the verapamil hydrochloride tablets highlighting the dependence of dissolution process on the formulation components other than the disintegrating agent. The results identified only one formulation as suitable for using the disintegration test, instead of the dissolution test, as drug product acceptance criteria and highlight the need for systematic studies before using the disintegration test, instead of the dissolution test as the drug acceptance criteria.
disintegration test; dissolution test; ICH Q6A; specification
The aims of this study are (1) to compare the disintegration efficiency, and (2) to develop a discriminating test model for the 3 classes of superdisintegrants represented by Ac-Di-Sol, Primojel, and Polyplasdone XL10. Using a digital video camera to examine the disintegration process of tablets containing the same wt/wt percentage concentration of the disintegrants, Ac-Di-Sol was found to disintegrate tablets rapidly into apparently primary particles; Primojel also apparently disintegrated tablets into primary particles but more slowly; Polyplasdone XL10 disintegrated tablets rapidly but into larger masses of aggregated particles. The differences in the size distribution generated in the disintegrated tablets likely contribute to the drug dissolution rate differences found for aspirin tablets with similar disintegration rates. The aspirin tablet matrix is proposed as a model formulation for disintegrant efficiency comparison and performance consistency testing for quality control purposes.
Superdisintegrants; aspirin tablet; disintegration; dissolution test
Aceclofenac, a non-steroidal antiinflammatory drug, is used for posttraumatic pain and rheumatoid arthritis. Aceclofenac fast-dispersible tablets have been prepared by direct compression method. Effect of superdisintegrants (such as, croscarmellose sodium, sodium starch glycolate and crospovidone) on wetting time, disintegration time, drug content, in vitro release and stability parameters has been studied. Disintegration time and dissolution parameters (t50% and t80%) decreased with increase in the level of croscarmellose sodium. Where as, disintegration time and dissolution parameters increased with increase in the level of sodium starch glycolate in tablets. However, the disintegration time values did not reflect in the dissolution parameter values of crospovidone tablets and release was dependent on the aggregate size in the dissolution medium. Stability studies indicated that tablets containing superdisintegrants were sensitive to high humidity conditions. It is concluded that fast-dispersible aceclofenac tablets could be prepared by direct compression using superdisintegrants.
Fast dispersible tablets; aceclofenac; croscarmellose sodium; sodium starch glycolate; crospovidone; disintegration time; dissolution
The aim of this paper was to study the effect of the granulate properties and tablet compression force on disintegrating force behavior in order to investigate the capability of the disintegrating force to characterize tablets that have the same composition but were manufactured in different conditions. Several tablets containing spironolactone in the external or internal granulated mixture of calcium carbonate and maize starch differing in particle size distribution, were prepared at 3 compression levels. The force developed by tablets during water uptake and disintegration was measured and plotted versus time. The curves obtained were analyzed by the Weibull equation in order to calculate the parameters characterizing the tablet disintegration kinetics. The disintegrating force time parameter, the maximum force developed, and the area under the curve were determined. In general, the reduction of time parameter value and/or the increase in maximum force developed corresponded to an acceleration in tablet disintegration. In addition, the area under the force curve increased in stronger tablets, monitoring in a sensitive way the tablet structural changes introduced by compression force. The results showed that the disintegrating force measurement can detect small changes in the structure of the tablet that cannot be discriminated by pharmacopoeia tests. The effect of manufacturing, in particular compression force, on tablet properties was quantified by the parameters of disintegrating force kinetics.
disintegrating force; spironolactone; tablet; granulation; compression force
Polacrilin Potassium NF is a commonly used weak cation exchange resin disintegrant in pharmaceutical tablets. The objective of this research was to evaluate the effects of sorbed moisture on physical characteristics and disintegrant performance of four brands of Polacrilin Potassium NF. The disintegrants were stored in five different relative humidity chambers and their dynamic vapor adsorption–desorption analysis, effect of moisture on their compressibility, compactability, particle size, morphology, water uptake rate, and disintegration ability were studied. Moisture seemed to plasticize the disintegrants, reducing their yield pressures. However, certain optimum amount of moisture was found to be useful in increasing the compactablity of the tablets containing disintegrants. The tablets, however, lost their tensile strengths beyond this optimum moisture content. Moisture caused two brands of the disintegrants to swell; however, two other brands aggregated upon exposure to moisture. Swelling without aggregation increased the water uptake, and in turn the disintegrant performance. However, aggregation probably reduced the porosities of the disintegrants, reducing their water uptake rate and disintegrant performance. Different brands of Polacrilin Potassium NF differed in the abilities to withstand the effects of moisture on their functionality. Effect of moisture on disintegrant performance of Polacrilin Potassium NF needs to be considered before its use in tablets made by wet granulation.
disintegrant performance; effect of moisture; functionality; ion exchange resins; physical characterization; polacrilin potassium NF; sorbed water; tablet disintegrants
Orodispersible tablets (ODTs) are tablet or wafer forms of medication that disintegrate in the mouth, aided only by saliva. ODTs rely on different fast dissolve/disintegration manufacturing technologies.
Disintegration time differences for several olanzapine ODT forms were investigated. Risperdal M-Tab® was included as a non-olanzapine ODT comparator.
Research Design and Methods
Eleven olanzapine ODT examples and orodispersible risperidone strengths were evaluated in vitro for formulation composition, manufacturing method, disintegration and dissolution characteristics, and formulation differences in comparison with freeze dried Zydis® ODT. Automated dissolution test equipment captured ODT dissolution rates by measuring real-time release of active ingredient. A high-speed video camera was used to capture tablet disintegration times in warm simulated saliva.
Main Outcome Measure
The main outcome measure was the disintegration and dissolution characteristics of the ODT formulations.
The ODT manufacturing method was associated with time to disintegrate; the fastest were freeze dried tablets, followed by soft compressed tablets and then hard/dense tablets. Olanzapine Zydis® was the only ODT that completely disintegrated in less than 4 s for all strengths (5, 10, 15, and 20 mg), followed by 5-mg Prolanz FAST® (12 s) and then risperidone ODT 4 mg (40 s). Reasons for slow dissolution of the olanzapine generics may include low product potency, excipient binding, excipient solubility, active ingredient particle size and incomplete disintegration.
Differences in the formulation and manufacturing process of olanzapine ODTs appear to have a strong influence on the disintegration time of the active compound; differences that may potentially impact their use in clinical practice.
Electronic supplementary material
The online version of this article (doi:10.1007/s40268-013-0030-8) contains supplementary material, which is available to authorized users.
The aim of this study was to evaluate the effect of increasing epinephrine load on the characteristics of fast-disintegrating sublingual tablets for the potential emergency treatment of anaphylaxis. Four tablet formulations, A, B, C, and D, containing 0%, 6%, 12%, and 24% of epinephrine bitartrate, respectively, and microcrystalline cellulose:low-substituted hydroxypropyl cellulose (9∶1), were prepared by direct compression, at a range of compression forces. Tablet weight variation, content uniformity, hardness, disintegration time, wetting time, and friability were measured for each formulation at each compression force. All 4 tablet formulations at each compression force were within the United States Pharmacopeia (USP) limits for weight variation and content uniformity. A linear increase in compression force resulted in an exponential increase in hardness for all formulations, a linear increase in disintegration and wetting times of A, and an exponential increase in disintegration and wetting times of B, C, and D. At a mean±SD hardness of ≥2.3±0.2 kg, all tablet formulations passed the USP friability test. At a mean±SD hardness of ≤3.1±0.2 kg, all tablet formulations resulted in disintegration and wetting times of <10 seconds and <30 seconds, respectively. Tablets with drug loads from 0% to 24% epinephrine can be formulated with hardness, disintegration times, and wetting times suitable for sublingual administration.
sublingual; transmucosal drug delivery; fastdisintegrating tablets; epinephrine; anaphylaxis
The purpose of this study was to investigate the efficiency of superdisintegrants in promoting tablet disintegration and drug dissolution under varied media pH. Significant reductions in the rate and extent of water uptake and swelling were observed for both sodium starch glycolate (Primojel) and croscarmellose sodium (Ac-Di-Sol) in an acidic medium (0.1 N HCl) but not for crospovidone NF (Polyplasdone XL10), a nonionic polymer. When Primojel and Ac-Di-Sol were incorporated in model formulations, a significant increase in tablet disintegration time was observed for slowly disintegrating tablets (lactose-based tablets) but not for the rapidly disintegrating tablets (dicalcium phosphate-based tablets). The dissolution rate of the model drug, hydrochlorothiazide, was found highly dependent on both tablet disintegration efficiency and the solubility of base material(s) in the testing medium. A laser diffraction particle size analyzer proved to be an effective tool for determining the intrinsic swelling of disintegrant particles in different media. Water uptake and swelling were confirmed as 2 important functions of superdisintegrants. The reduced water uptake and swelling capacity of disintegrants containing ionizable substituents in an acidic medium can potentially jeopardize their efficiency in promoting tablet disintegration and the drug dissolution rate.
superdisintegrants; particle swelling; liquid uptake; disintegration medium pH; dissolution medium pH; hydrochlorothiazide
The interest in and need for formulating miconazole nitrate (MN), a broad-spectrum antifungal, as an oral disintegrating tablet for treatment of some forms of candidiasis have increased. Formulation of MN in this dosage form will be more advantageous, producing dual effect: local in the buccal cavity and systemic with rapid absorption. Four formulations were prepared utilizing the foam granulation technique. The prepared tablets were characterized by measuring the weight uniformity, thickness, tensile strength, friability, and drug content. In addition, tablet disintegration time, in vitro dissolution, and in vivo disintegration time were also evaluated. Stability testing for the prepared tablets under stress and accelerated conditions in two different packs were investigated. Each pack was incubated at two different elevated temperature and relative humidity (RH), namely 40 ± 2°C/75 ± 5% RH and 50 ± 2°C/75 ± 5% RH. The purpose of the study is to monitor any degradation reactions which will help to predict the shelf life of the product under the defined storage conditions. Finally, in vivo study was performed on the most stable formula to determine its pharmacokinetic parameters. The results revealed that all the prepared tablets showed acceptable tablet characteristics and were stable under the tested conditions. The most stable formula was that containing magnesium stearate as lubricant, hydrophobic Aerosil R972 as glidant, low urea content, mannitol/microcrystalline cellulose ratio 2:1, and 9% Plasdone XL100 as superdisintegrant. The in vivo results revealed that the tested formula showed rapid absorption compared to the physical blend (tmax were 1 and 4 h, respectively), while the extent of absorption was almost the same.
accelerated stability testing; bioavailability; foam granulation technique; miconazole nitrate; oral disintegrating tablet
The objective of this work was to apply a new apparatus for the assay of the drug release from lozenge tablet with a potential use in the treatment of oral candidosis and another conditions connected to microbial etiopathology in the oral cavity or as an antiplaque factor. Also, an approach to comparison of the applied method with the classical paddle apparatus method was performed. Tablets containing chlorhexidine dihydrochloride were formulated with granulated sorbitol of different grades (diameter of 110, 180, 480, and 650 μm, respectively), lactose, and magnesium stearate as excipients. Tablets were obtained through direct compression, and uniformity of weight, friability, breaking strength, disintegration, and release rate were evaluated. The disintegration times ranged between 10 and 21 min. In the next stage of the study, the release of chlorhexidine from lozenges prepared with granulated sorbitol grade 110 μm and different amounts of lactose and magnesium stearate was assessed. Two stages were observed during the release of chlorhexidine dihydrochloride from the lozenges, assayed by the classical paddle apparatus method II USP. In the first stage, release rates were between 2.6 × 10−2 and 4.7 × 10−2 min−1, in the second stage between 1.7 × 10−3 and 7.7 × 10−3 min−1. In the case of the in-house method, the release was near to first-order kinetics through the entire release experiment, with rate constants between 3.6 × 10−2 and 6.6 × 10−2 min−1. The sorbitol granulate of granules with diameter 110 μm was found to be most suitable for the lozenges with chlorhexidine dihydrochloride and lactose. The in-house release method, proposed in this work, seems to be more realistic for the preliminary assessment of predicted drug concentrations in the oral cavity after the intake of a lozenge.
chlorhexidine; lactose; lozenges; magnesium stearate; release rate; sorbitol
The recent challenge in orally disintegrating tablets (ODT) manufacturing encompasses the compromise between instantaneous disintegration, sufficient hardness, and standard processing equipment. The current investigation constitutes one attempt to fulfill this challenge. Maltodextrin, in the present work, was utilized as a novel excipient to prepare ODT of meclizine. Tablets were prepared by both direct compression and wet granulation techniques. The effect of maltodextrin concentrations on ODT characteristics—manifested as hardness and disintegration time—was studied. The effect of conditioning (40°C and 75% relative humidity) as a post-compression treatment on ODT characteristics was also assessed. Furthermore, maltodextrin-pronounced hardening effect was investigated using differential scanning calorimetry (DSC) and X-ray analysis. Results revealed that in both techniques, rapid disintegration (30–40 s) would be achieved on the cost of tablet hardness (about 1 kg). Post-compression conditioning of tablets resulted in an increase in hardness (3 kg), while keeping rapid disintegration (30–40 s) according to guidance of the FDA for ODT. However, direct compression-conditioning technique exhibited drawbacks of long conditioning time and appearance of the so-called patch effect. These problems were, yet, absent in wet granulation-conditioning technique. DSC and X-ray analysis suggested involvement of glass-elastic deformation in maltodextrin hardening effect. High-performance liquid chromatography analysis of meclizine ODT suggested no degradation of the drug by the applied conditions of temperature and humidity. Overall results proposed that maltodextrin is a promising saccharide for production of ODT with accepted hardness-disintegration time compromise, utilizing standard processing equipment and phenomena of phase transition.
disintegration time; maltodextrin; meclizine; orally disintegrating tablets; phase transition
The aim of this study was to investigate the ability of liquid loadable tablets (LLT) to be loaded with a self-microemulsifying drug delivery system (SMEDDS) containing cyclosporine (CyA). LLT were prepared by direct compression of the porous carrier magnesium aluminometasilicate and subsequently loaded with SMEDDS by a simple absorption method. SMEDDS was evaluated regarding visual appearance and droplet size distribution after dispersion in aqueous media. The developed SMEDDS was found to be similar to Neoral®. LLT were characterized before and after loading regarding weight variation, tablet hardness, disintegration time, and in vitro drug release. It was found that LLT with high porosities suitable for liquid loading and further processing could be prepared. Adding a tablet disintegrant was found to improve in vitro drug release. Additionally, the volume-based loading capacity of LLT was evaluated and found to be comparable to soft gelatin and hard two-piece capsules. Furthermore, the pharmacokinetic performance of CyA from loaded LLT was tested in two PK-studies in dogs. Absorption of CyA from SMEDDS loaded into LLT was found in the first study to be significantly lower than the absorption of CyA from SMEDDS filled into a capsule. However, addition of a superdisintegrant improved the absorption markedly. The bioavailability of CyA from SMEDDS loaded into disintegrating LLT was found in the second study to be at the same level as from capsule formulation. In conclusion, the LLT technology is therefore seen as a promising alternative way of achieving a solid dosage form from liquid drug delivery systems.
cyclosporine; drug carrier; liquid loadable tablets; SMEDDS
The purpose of this investigation was to develop a rapidly disintegrating calcium carbonate (CC) tablet by direct compression and compare it with commercially available calcium tablets. CC tablets were formulated on a Carver press using 3 different forms of CC direct compressed granules (Cal-Carb 4450®, Cal-Carb 4457®, and Cal-Carb 4462®). The breaking strength was measured using a Stokes-Monsanto hardness tester. The disintegration and dissolution properties of the tablets were studied using USP methodology. The calcium concentration was determined by an atomic absorption spectrophotometer. Scanning electron microscopy was used to evaluate the surface topography of the granules and tablets. Breaking strength of Cal-Carb 4450®, Cal-Carb 4457®, and Cal-Carb 4462® tablets was in the range of 7.2 to 7.7 kg, as compared with a hardness of 6.2 kg and 10 kg for the commercially available calcium tablets Citracal® and Tums®, respectively. The disintegration time for the tablets presented in the order earlier was 4.1, 2.1, 1.9, 2.9, and 9.7 minutes, respectively. The dissolution studies showed that all formulations released 100% of the elemental calcium in simulated gastric fluid in less than 20 minutes. In summary, this study clearly demonstrated that quick disintegrating CC tablets can be formulated without expensive effervescence technology.
Calcium Carbonate Tablets; Quick Disintegrating; Effervescence
Coenzyme Q10 (CoQ10) has been widely commercially available in Japan as a dietary and health supplement since 2001 and is used for the prevention of lifestyle-related diseases induced by free radicals and aging. We evaluated CoQ10 supplements to ensure that these supplements can be used effectively and safely. Commercially available products were selected and assessed by the quality control tests specified in the Japanese Pharmacopoeia XV. When the disintegration time of CoQ10 supplements was measured, a few tested supplements did not completely disintegrate even after incubation in water for an hour at 37°C. In the content test, many samples were well controlled. However, a few supplements showed low recovery rates of CoQ10 as compared to manufacturer’s indicated contents. Among soft capsule and liquid supplements, the reduced form of CoQ10 (H2CoQ10), as well as the oxidized form, was detected by HPLC with electrochemical detector. The results for experimental formulated CoQ10 supplements demonstrated that H2CoQ10 was produced by the interaction of CoQ10 with vitamins E and/or C. From these results, we concluded that quality varied considerably among the many supplement brands containing CoQ10. Additionally, we also demonstrated that H2CoQ10 can be detected in some foods as well as in CoQ10 supplements.
coenzyme Q10; ubiqinol-10; quality control; dietary and health supplement; food
Poly(vinyl alcohol) (PVA)-based formulations are used for pharmaceutical tablet coating with numerous advantages. Our objective is to study the stability of PVA-based coating films in the presence of acidic additives, alkaline additives, and various common impurities typically found in tablet formulations. Opadry® II 85F was used as the model PVA-based coating formulation. The additives and impurities were incorporated into the polymer suspension prior to film casting. Control and test films were analyzed before and after exposure to 40°C/75% relative humidity. Tests included film disintegration, size-exclusion chromatography, thermal analysis, and microscopy. Under stressed conditions, acidic additives (hydrochloric acid (HCl) and ammonium bisulfate (NH4HSO4)) negatively impacted Opadry® II 85F film disintegration while NaOH, formaldehyde, and peroxide did not. Absence of PVA species from the disintegration media corresponded to an increase in crystallinity of PVA for reacted films containing HCl. Films with NH4HSO4 exhibited slower rate of reactivity and less elevation in melting temperature with no clear change in melting enthalpy. Acidic additives posed greater risk of compromise in disintegration of PVA-based coatings than alkaline or common impurities. The mechanism of acid-induced reactivity due to the presence of acidic salts (HCl vs. NH4HSO4) may be different.
acid salts and stability; pharmaceutical coating; polyethylene glycol; poly(vinyl alcohol)
The summary is that the high humidity impaired the disintegrant property of α-cellulose in all 3 tablets tested. Tablets of aspirin, which is the more hygroscopic drug, were also more sensitive to the humidity effect, while tablets of chloroquine phosphate, which is a water-soluble drug, were the least sensitive to the humidity effect. The results permit the conclusion that moisture uptake with subsequent gelling of the α-cellulose is the mechanism of impairment of its disintegrant property. The tablets would not normally be stored under an RH as high as 100%, nevertheless, the results of the accelerated stability study have underscored the need to protect tablets containing α-cellulose as disintegrant from moisture.
disintegrant property of α-cellulose; humidity effect; tablet hydration
Acid modified starches obtained from two species of yam tubers namely white yam – Dioscorearotundata L. and water yam – D. alata L. DIAL2 have been investigated as intra- and extra-granular disintegrants in paracetamol tablet formulations. The native starches were modified by acid hydrolysis and employed as disintegrant at concentrations of 5 and 10% w/w and their disintegrant properties compared with those of corn starch BP. The tensile strength and drug release properties of the tablets, assessed using the disintegration and dissolution (t50 and t80 – time required for 50% and 80% of paracetamol to be released) times, were evaluated. The results showed that the tensile strength and the disintegration and dissolution times of the tablets decreased with increase in the concentration of the starch disintegrants. The acid modified yam starches showed better disintegrant efficiency than corn starch in the tablet formulations. Acid modification appeared to improve the disintegrant efficiency of the yam starches. Furthermore, tablets containing starches incorporated extragranularly showed faster disintegration but lower tensile strength than those containing starches incorporated intragranularly. This emphasizes the importance of the mode of incorporation of starch disintegrant.
Yam starch; Corn starch; Acid modification; Disintegrant properties; Tablets
There is a need for reliable methods of glucose measurement in different environmental conditions. The objective of this in vitro study was to evaluate the performance of the Enlite® Sensor when connected to either the iPro™ Continuous Glucose Monitor recording device or the Guardian® REAL-Time transmitting device, in hypobaric and hyperbaric conditions.
Sixteen sensors connected to eight iPro devices and eight Guardian REAL-Time devices were immersed in three beakers containing separate glucose concentrations: 52, 88, and 207 mg/dl (2.9, 4.9, and 11.3 mmol/liter). Two different pressure tests were conducted: a hypobaric test, corresponding to maximum 18000 ft/5500 m height, and a hyperbaric test, corresponding to maximum 100 ft/30 m depth. The linearity of the sensor signals in the different conditions was evaluated.
The sensors worked continuously, and the sensor signals were collected without interruption at all pressures tested. When comparing the input signals for glucose (ISIGs) and the different glucose concentrations during altered pressure, linearity (R2) of 0.98 was found. During the hypobaric test, significant differences (p < .005) were seen when comparing the ISIGs during varying pressure at two of the glucose concentrations (52 and 207 mg/dl), whereas no difference was seen at the 88 mg/dl glucose concentration. During the hyperbaric test, no differences were found.
The Enlite Sensors connected to either the iPro or the Guardian REAL-Time device provided values continuously. In hyperbaric conditions, no significant differences were seen during changes in ambient pressure; however, during hypobaric conditions, the ISIG was significantly different in the low and high glucose concentrations.
barometric pressure; continuous glucose monitoring; diabetes mellitus; glucose; sensor
The potency, disintegration and dissolution characteristics of 23 brands of phenylbutazone tablets were determined. Five (21.7%) of the 23 brands failed to comply with the minimum requirements of the compendia or the regulations appended to the Food and Drugs Act. The in vitro characteristics of four brands were substantially different from those that disintegrated and released the drug satisfactorily. The in vivo characteristics of three of the four brands were compared with those observed for a pharmaceutically acceptable product. The latter product released the drug to the blood quickly, but the former products released the drug only after the tablets had been in the body for six to eight hours and, in the case of one product, released quantities much below those that would be acceptable to the physician. These results show that different products containing the same drug are not necessarily equivalent. This is contrary to the generic equivalency hypothesis which assumes that all products comply with specifications and, therefore, must be clinically effective.
The purpose of this research was to obtain directly compressible agglomerates of naproxen containing disintegrant by spherical crystallization technique. Acetone–water containing hydroxypropyl celloluse (HPC) and disintegrant was used as the crystallization system. In this study croscarmellose sodium (Ac–Di–Sol) was employed as disintegrant. The agglomerates were characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (XRPD), and scanning electron microscopy and were evaluated for flow, packing and tableting properties and drug release. The growth of particle size and the spherical form of the agglomerates resulted in formation of products with good flow and packing properties. The improved compaction properties of the agglomerated crystals were due to their fragmentation occurred during compression. DSC and XRPD studies showed that naproxen particles, crystallized in the presence of HPC and Ac–Di–Sol did not undergo structural modifications. The dissolution rate of naproxen from tablets made of naproxen–(Ac–Di–Sol) agglomerates was enhanced significantly because of including the disintegrant in to the particles. This was attributed to an increase in the surface area of the practically water insoluble drug is exposed to the dissolution medium. In conclusion the spherical crystallization technique developed in this study is suitable for obtaining agglomerates of drug with disintegrant.
direct tableting; disintegration; naproxen; spherical crystallization
In ecotoxicological and environmental studies Lemna spp. are used as test organisms due to their small size, rapid predominantly vegetative reproduction, easy handling and high sensitivity to various chemicals. However, there is not much information available concerning spatial and temporal stability of experimental set-ups used for Lemna bioassays, though this is essential for interpretation and reliability of results. We therefore investigated stability and natural variability of a Lemna gibba bioassay assessing area-related and frond number-related growth rates under controlled laboratory conditions over about one year.
Lemna gibba L. was grown in beakers with Steinberg medium for one week. Area-related and frond number-related growth rates (r(area) and r(num)) were determined with a non-destructive image processing system.
To assess inter-experimental stability, 35 independent experiments were performed with 10 beakers each in the course of one year. We observed changes in growth rates by a factor of two over time. These did not correlate well with temperature or relative humidity in the growth chamber.
In order to assess intra-experimental stability, we analysed six systematic negative control experiments (nontoxicant tests) with 96 replicate beakers each. Evaluation showed that the chosen experimental set-up was stable and did not produce false positive results. The coefficient of variation was lower for r(area) (2.99%) than for r(num) (4.27%).
It is hypothesised that the variations in growth rates over time under controlled conditions are partly due to endogenic periodicities in Lemna gibba. The relevance of these variations for toxicity investigations should be investigated more closely. Area-related growth rate seems to be more precise as non-destructive calculation parameter than number-related growth rate. Furthermore, we propose two new validity criteria for Lemna gibba bioassays: variability of average specific and section-by-section segmented growth rate, complementary to average specific growth rate as the only validity criterion existing in guidelines for duckweed bioassays.
We sought to evaluate whether U.S. Pharmacopeia (USP) apparatus 3 can be used as an alternative to USP apparatus 2 for dissolution testing of immediate-release (IR) dosage forms. Highly soluble drugs, metoprolol and ranitidine, and poorly soluble drugs, acyclovir and furosemide, were chosen as model drugs. The dissolution profiles of both innovator and generic IR products were determined using USP apparatus 2 at 50 rpm and apparatus 3 at 5, 15, and 25 dips per minute (dpm). The dissolution profiles from USP apparatus 3 were compared to those from USP apparatus 2 using the f2 similarity test. The dissolution profile from USP apparatus 3 generally depends on the agitation rate, with a faster agitation rate producing a faster dissolution rate. It was found that USP apparatus 3 at the extreme low end of the possible agitation range, such as 5 dpm, gave hydrodynamic conditions equivalent to USP apparatus 2 at 50 rpm. With appropriate agitation rate, USP apparatus 3 can produce similar dissolution profiles to USP apparatus 2 or distinguish dissolution characteristics for the IR products of metoprolol, ranitidine, and acyclovir. Incomplete dissolution was observed for the furosemide tablets using USP apparatus 3. Although it is primarily designed for the release testing of extended-release products, USP apparatus 3 may be used for the dissolution testing of IR products of highly soluble drugs, such as metoprolol and ranitidine, and some IR products of poorly soluble drugs, such as acyclovir. USP apparatus 3 offers the advantages of avoiding cone formation and mimicking the changes in physiochemical conditions and mechanical forces experienced by products in the gastrointestinal tract.
Dissolution; USP apparatus 2; USP apparatus 3; Immediate-Release; and Product
Recent interest in the development of drug particle-laden strip-films suggests the need for establishing standard regulatory tests for their dissolution. In this work, we consider the dissolution testing of griseofulvin (GF) particles, a poorly water-soluble compound, incorporated into a strip-film dosage form. The basket apparatus (USP I) and the flow-through cell dissolution apparatus (USP IV) were employed using 0.54% sodium dodecyl sulfate as the dissolution medium as per USP standard. Different rotational speeds and dissolution volumes were tested for the basket method while different cell patterns/strip-film position and dissolution media flow rate were tested using the flow-through cell dissolution method. The USP I was not able to discriminate dissolution of GF particles with respect to particle size. On the other hand, in the USP IV, GF nanoparticles incorporated in strip-films exhibited enhancement in dissolution rates and dissolution extent compared with GF microparticles incorporated in strip-films. Within the range of patterns and flow rates used, the optimal discrimination behavior was obtained when the strip-film was layered between glass beads and a flow rate of 16 ml/min was used. These results demonstrate the superior discriminatory power of the USP IV and suggest that it could be employed as a testing device in the development of strip-films containing drug nanoparticles.
BCS class II; dissolution; drug nanoparticles; flow-through cell; pharmaceutical strip-films