Development and Validation of a Dissolution Test for Meloxicam and Pridinol Mesylate from Combined Tablet Formulation

The association of meloxicam and pridinol is indicated for treating muscular contractures and low back pain. A dissolution test for the meloxicam-pridinol combined tablet formulation was developed and validated, using a suitable HPLC method for simultaneously quantitating both dissolved drugs. The optimized conditions include the use of USP apparatus 2 at a paddle rotation rate of 75 rpm and 900 ml of 50 mM phosphate buffer (pH= 7.5) as dissolution medium, at 37.0±0.5°. The test, which demonstrated to be robust against small changes in bath temperature, paddle rotation speed and pH of the dissolution medium, was applied to two different brands of tablets; the corresponding dissolution profiles were constructed and both brands showed to dissolve at least 75% of the drugs at the 45 min time point.     

Development and validation of dissolution test for lopinavir, a poorly water-soluble drug, in soft gel capsules, based on in vivo data

The objective of the present study was to develop and validate a dissolution test for lopinavir soft gel capsules (Kaletra), using a simulated absorption profile based on in vivo data. Different conditions such as surfactant concentration, apparatus and rotation speed were evaluated. In vivo release profiles were obtained from the literature. The fraction (and percentage) of dose absorbed (FA) was calculated by using Wagner-Nelson method. The best in vitro dissolution profile was obtained using Apparatus 2 (paddle) at 25 rpm, 1000 ml of medium with 2.3% of sodium lauryl sulfate and pH 6.0. Under these conditions a level-A in vitro-in vivo correlation (IVIVC) was obtained (r = 0.997). The in vitro dissolution samples were analyzed using a HPLC method and the validation was performed according to USP protocol. The method showed accuracy, precision, linearity and specificity within the acceptable range. Both the HPLC method and the in vitro dissolution method were validated and could be used to evaluate the release profile of lopinavir soft gel capsules.     

中国药典2010年版卡托普利片溶出度检验方法研究

目的 改进卡托普利片溶出度检测方法。方法 采用转篮法测定卡托普利片溶出度,以0.01 mol·L-1盐酸溶液900 mL为溶出介质,转速50 r·min-1,经20 min取样。结果 采用USP对A、B厂的卡托普利片进行溶出度检测,溶出曲线存在明显的差异;B厂产品不符合规定,且批内均一性也存在很大差异。结论 改进的方法极大地抑制了卡托普利的降解,对改进制剂处方工艺及控制产品质量提供了有益的参考,可用于卡托普利片的溶出度检查。     

伐昔洛韦缓释片体外释放速率与人体内吸收速率的相关性

目的:研究伐昔洛韦缓释片体外释放速率与人体内吸收速率的相关性。方法:以水为释放介质,测定伐昔洛韦缓释片的体外释放速率;采用Wagner-Nelson法计算单剂量口服缓释片后体内吸收分数,考察吸收相体内吸收与体外释放的相关性。结果:伐昔洛韦缓释片体内吸收分数(f_a)与体外释放速率(f_r)的关系为:f_a=2.11f_r -20.12,r=0.994 0(n=5)。结论:伐昔洛韦缓释片人体内外相关性良好(P<0.001)。     

In-vivo and In-vitro Correlation for Delayed-release Behaviour of a Molsidomine/O-carboxymethyl-O-ethyl-β-cyclodextrin Complex in Gastric Acidity-controlled Dogs

The in-vivo absorption behaviour of molsidomine from the delayed-release tablets of an O-carboxy-methyl-O-ethyl-β-cyclodextrin complex was investigated using gastric acidity-controlled dogs under fasted and non-fasted conditions. The in-vitro release profiles were generated by changing the pH of the dissolution medium at different rotation paddle speeds. The absorptivity of molsidomine in the high acidity dog was correlated with the pH-changed release profile (pH 1·2 to 7·0 after 2 h), whereas that in the low acidity dog was correlated with the release profile at a constant pH of 7·0. The absorption in fasted dogs was well correlated with the in-vitro release at the low-rotation paddle speed (< 5 rev min^?1), whereas that in the non-fasted dogs was correlated with that of high rotation (100 rev min^?1). The present results suggested that the in-vivo delayed-release behaviour of the complex is predictable from the in-vitro release profiles generated using pH-variable dissolution testing apparatus at different rotation speeds of the paddle.     

Development and validation of a dissolution test method for vitamin A in dietary supplement tablets

A dissolution test method and an analytical procedure by HPLC were developed and validated for evaluation of the dissolution behavior of dietary supplements tablets containing vitamin A in the forms of retinyl acetate or retinyl palmitate. Seven different commercially available products containing retinyl acetate or retinyl palmitate were selected for this study. A dissolution medium containing 1% (w/v) Octoxynol 9 (Triton X-100) and 1% (w/v) (+)-sodium α-ascorbate in 0.05 M phosphate buffer, pH 6.8, was found suitable to ensure sink conditions and chemical stability for both retinyl acetate and retinyl palmitate. Two rotation speeds, 50 and 75 rpm, were evaluated with USP Apparatus 2 and 900 ml dissolution medium. Dissolution profiles were generated over 120 min. Dissolution samples were analyzed with a reversed-phase HPLC method with UV detection at 325 nm. Each product was also assayed for vitamin A content according to USP 32–NF 27. The results from 45 min to the last time point of the dissolution tests performed at 75 rpm were consistent with the Assay results. The dissolution test described here could be proposed as a pharmacopeial standard to assess the performance of tablet formulations containing vitamin A as retinyl esters.     

Designing biorelevant dissolution tests for lipid formulations: Case example – Lipid suspension of RZ-50

Biorelevant dissolution test methods for lipid formulations of RZ-50, an experimental Roche compound, were developed and compared with standard compendial methods in terms of their in vivo predictability. Release of RZ-50, a poorly soluble weakly acidic drug, from lipid suspensions filled in soft gelatin capsules was studied in compendial and biorelevant media using the USP Apparatus 2 (paddle method) and the USP Apparatus 3 (Bio-Dis method). Pharmacokinetic data were obtained in dogs after oral administration of a single 2.5mg dose of RZ-50 soft gelatin capsules in the postprandial state. Level A IVIVC analysis and curve comparison of fraction drug dissolved vs. absorbed using the Weibull distribution were used to evaluate the in vitro methods in terms of their ability to fit the in vivo plasma profiles. Very low drug release was observed with the paddle method owing to poor dispersibility of the lipids in the dissolution media, whereas the Bio-Dis method hydrodynamics facilitated release of the drug by emulsifying the formulation in the medium. The best IVIVC was obtained using a dissolution medium representing fed gastric conditions in combination with the Bio-Dis method. Curve comparisons of the fraction drug absorbed and the fraction drug dissolved profiles based on Weibull distribution fits yielded similar results. The Bio-Dis/biorelevant in vitro method appears to be suitable for this type of lipid formulation.     

Evaluation of USP apparatus 3 for dissolution testing of immediate-release products

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 f ₂ 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.     

Comparative in vitro dissolution study of carbamazepine immediate-release products using the USP paddles method and the flow-through cell system

Dissolution profiles of four carbamazepine immediate-release generic products (200 mg tablets) and the reference product Tegretol® were evaluated using the USP paddles method and an alternative method with the flow-through cell system, USP Apparatus 4. Under official conditions all products met the Q specification, dissolution profiles of generic products were similar to the dissolution profile of the reference product (f₂ > 50) and model-independent parameters showed non significant differences to the reference product except mean dissolution time for product A (p < 0.05). On the other hand, when the flow-through cell system was used, none of the products met the pharmacopeial specification at 15 min and product A did not reach dissolution criteria at 60 min, dissolution profiles of all generic products were not similar to the reference product profile (f₂ < 50) and all model-independent parameters showed significant differences compared to the reference product (p < 0.05). Weibull’s model was more useful for adjusting the dissolution data of all products in both USP apparatuses and Td values showed significant differences compared to the reference product (p < 0.05) when USP Apparatus 4 was used. These results indicate that the proposed method, using the flow-through cell system, is more discriminative in evaluating both, rate and extent of carbamazepine dissolution process from immediate-release generic products.     

Dissolution test for citalopram in tablets and comparison of in vitro dissolution profiles.

A dissolution test for tablets containing 20 mg of citalopram was developed and validated using a reverse-phase liquid chromatographic method and this dissolution test was applied to compare dissolution profiles. The sink conditions, filters, stability of the drug and specificity on different dissolution media were tested to choose a discriminatory dissolution method which uses USP apparatus 1 with baskets rotating at 50 rpm, 900 ml of deaerated 0.1 M hydrochloric acid (HCl) as the dissolution medium. The quantitation method was also adapted and validated. The parameters of difference factor, similar factor, according to current FDA guidelines, and dissolution efficiency were employed to compare dissolution profiles. The dissolution test developed and validated was adequate for its purposes and could be applied for quality control of citalopram tablets, since there is no monograph to citalopram in tablets, this work can be used to help pharmocopoeias.     

Development and validation of dissolution test for ritonavir soft gelatin capsules based on in vivo data

The purpose of the study was to develop and validate a dissolution procedure for ritonavir soft gelatin capsules (Norvir) based on in vivo data. Several conditions such as medium composition, pH, surfactant concentration and rotation speed were evaluated. The method was carried out using the same batch of Norvir used in a bioequivalence study and the in vivo data were used to select the best dissolution test conditions based on in vitro-in vivo correlation (IVIVC). The dissolution test was validated using a high-performance liquid chromatographic method (HPLC). For this formulation, the best dissolution conditions were achieved using paddle, 900ml of medium containing water with 0.7% (w/v) of sodium lauryl sulfate at a rotation speed of 25rpm. Under these conditions a significant linear relationship between fraction of ritonavir absorbed and dissolved was obtained (R(2)=0.993) and a level A IVIVC was established. In the HPLC method a relative standard deviation for intra-day precision was <1.6% and for inter-day precision was <1.4%. Accuracy was from 98.5% to 101.6% over the concentration range required for the dissolution test (4.0-124.0microg/ml). Both the HPLC method and the dissolution test are validated and could be used to evaluate the dissolution profile of ritonavir soft gelatin capsules.     

Preliminary observations on dissolution and bioavailability of triamterene–hydrochlorothiazide combination products

The dissolution profiles of two brands of triamterene–hydrocholorthiazide (TRM–HCT) combination tablets and two brands of TRM–HCT combination capsules were studied using the USP paddle method at 100 rev min^?1 in acid medium (0·1 N). The tablets represent two products marketed in Germany, whereas the capsules represent the approved innovator's product and an unapproved generic product. The tablets dissolved almost 100 per cent in 15 min whereas the capsules dissolved less than 25 per cent in 60 min. A pilot bioavailability study was carried out in four normal healthy male volunteers. Urine samples were collected over a 48 h period and analysed for TRM, its major metabolite TRM-sulfate, and HCT using HPLC methods. The dissolution characteristics of TRM can be associated with the total drug excretion (absorption) of the product. On the other hand, the excretion (absorption) of HCT was independent of dissolution characteristics of the products. However, in TRM–HCT combination product, there appears to be a 50 per cent reduction in HCT excretion (absorption) when compared to the reported excretion (absorption) from a marketed single-entity product.     

Comparison of dissolution rates of ibuprofen tablets

The dissolution profiles of 600mg ibuprofen tablets from four manufacturers have been compared with those of Boots's Brufen. The latter showed rapid dissolution in phosphate buffer pH 7.2 (the USP method) such that 50 per cent was dissolved in 3.9 ± 0.9 min and 90 per cent in 7.7 ± 1.9 min. Tablets from one manufacturer showed similar dissolution characteristics to those of Boots while the other manufacturers' products dissolved more slowly. Five out of 48 tablets from one manufacturer did not achieve the USP specification of 70 per cent dissolved by 30 min. Differences in dissolution rates have been shown to affect speed of action in some products. A study is required to determine the analgesic properties of ibuprofen tablets that dissolve at different rates.     

Influence of in vitro test conditions on release of aspirin from commercial tablets.

The influence of in vitro test conditions on the release of aspirin from commercial tablets was assessed with a USP rotating-basket dissolution apparatus. Three types of aspirin tablets were evaluated: plain, buffered, and microencapsulated. The variables investigated were stirring speed, pH, and volume and temperature of the dissolution medium. Plain tablets gave the best dissolution profiles under all experimental conditions, except at pH 3. Microencapsulated tablets showed sustained release. For all three types of tablets, faster dissolution was observed at pH 4.5 compared with that in artificial gastric juices. Increasing the stirring rate increased the dissolution rate, an effect most pronounced for plain tablets. Very similar dissolution curves were obtained when the dissolution test was conducted in 500 and 900 mL of dissolution media regardless of the pH of the media. No significant difference in dissolution profiles was observed when the effect of temperature was investigated. The dissolution data were evaluated on the basis of theoretical dissolution equations and by linear transformation of dissolution curves. Highly significant linear correlation coefficients revealed that the cube root equation could be used to describe drug release in artificial gastric juices, regardless of tablet type. When pH 4.5 buffer solution was used as the dissolution medium, different kinetic models were applicable.     

Multiple level C in vitro/in vivo correlation of dissolution profiles of two thyroxine tablets with pharmacokinetics data obtained from patients treated for hypothyroidism

In a previous study aimed to compare the bioavailability of two levothyroxine tablets, we found a good relation between their pharmacokinetics parameters and dissolution profiles, employing the USP dissolution conditions in use at that time (24th edition). Despite the formulations were considered bioequivalent, the test product presented values of AUC and concentrations at steady-state significantly lower (about 10%) than the reference ones. The purpose of the present study was to evaluate if the actual pharmacopeial conditions (with alterations introduced in the first supplement of USP 24) would also allow a good correlation between bioavailability and dissolution data. The partial AUCs were correlated with cumulative levothyroxine amount dissolved at three different times, for each dissolution condition. Employing the old method, test tablets had a slower dissolution rate than the reference ones, resulting in a quite good multiple level C in vitro/in vivo (IVIV) correlation. On the other hand, the very fast dissolution profiles obtained in the actual condition lead to a worse IVIV correlation. Present work indicates that the mild conditions proposed in the older US Pharmacopeia were better than the actual in order to discriminate dissolution profiles of levothyroxine tablets which present subtle, but significant, differences in their pattern of absorption.     

阿奇霉素片溶出曲线一致性评价研究

摘要：目的 建立阿奇霉素片溶出曲线测定方法,评价国产仿制阿奇霉素片与原研药在4种不同pH的溶出介质中的体外溶 出行为。方法 采用桨法,转速为75r/min,分别以pH2.0盐酸溶液、pH4.5磷酸盐缓冲液、pH6.0磷酸盐缓冲液和pH6.8磷酸盐缓 冲液为溶出介质,溶出介质体积为900mL;采用UPLC法测定阿奇霉素溶出度,并计算累积溶出量,绘制溶出曲线;评价溶出 曲线的相似度。结果 在4种不同pH的溶出介质中,国产和原研阿奇霉素片均在15min内溶出量达到了85%以上,说明两批国内 仿制产品与原研药溶出行为基本一致,判定相似。结论 本方法适用于阿奇霉素片仿制药的溶出曲线测定,可为阿奇霉素片的 质量一致性评价提供参考。     

Development and Validation of Discriminating and Biorelevant Dissolution Test for Lornoxicam Tablets

The establishment of biorelevant and discriminating dissolution procedure for drug products with limited water solubility is a useful technique for qualitative forecasting of the in vivo behavior of formulations. It also characterizes the drug product performance in pharmaceutical development. Lornoxicam, a BCS class-II drug is a nonsteroidal antiinflammatory drug of the oxicam class, has no official dissolution media available in the literature. The objective of present work was to develop and validate a discriminating and biorelevant dissolution test for lornoxicam tablet dosage forms. To quantify the lornoxicam in dissolution samples, UV spectrophotometric method was developed using 0.01M sodium hydroxide solution as solvent at λ_ma×376 nm. After evaluation of saturation solubility, dissolution, sink conditions and stability of lornoxicam bulk drug in different pH solutions and biorelevant media, the dissolution method was optimized using USP paddle type apparatus at 50 rpm rotation speed and 500 ml simulated intestinal fluid as discriminating and biorelevant dissolution medium. The similarity factor (f₂) were investigated for formulations with changes in composition and manufacturing variations, values revealed that dissolution method having discriminating power and method was validated as per standard guidelines. The proposed dissolution method can be effectively applied for routine quality control in vitro dissolution studies of lornoxicam in tablets and helpful to pharmacopoeias.     

Effect of Hydrodynamic Environment on Tablets Dissolution Rate

The main objective of this research was to develop an experimental method to apply well‐defined flow fields to solid dosage forms, to study the rate process underlying tablet dissolution, and to better understand the role of external hydrodynamic condition on mass transfer rate and film thickness during dissolution. Two drugs models, Theophylline (class 1) and Naproxen (class 2), were selected and formulated into conventional tablets containing 105 mg Theophylline or 300 mg Naproxen using the wet granulation method. Tablets were tested for dissolution using both the basket and paddle methods at different rotational speed of 25, 50, 75, and 100 rpm. In general, the paddle method gave higher dissolution rates than the basket method and as the velocity of rotation was increased, drug release was also increased. Six different paddles and a tablet holder were designed and used to test dissolution rate. The rate of dissolution was dependent on the tablet surface area exposed to the dissolution medium, and on the shape, diameter, and area of the paddles used. Theophylline tablets showed increased mass transfer rate and decreased film thickness as basket rotation speed was increased. At 25 rpm, the mass transfer coefficient was 0.684 × 10^{? 4} cm/sec and film thickness was 12.003 × 10^{? 2} cm; at 100 rpm, the mass transfer coefficient was 3.884 × 10^{? 4} cm/sec and film thickness was 2.114 × 10^{? 2} cm. Paddle values tested at the same speed showed higher mass transfer coefficient and lower film thickness for Theophylline and Naproxen tablets. P values obtained by modification of the Stokes‐Einstein equation showed that diffusion is the rate‐limiting step to drug release and not mass transfer. This study demonstrated that hydrodynamic condition, type of dissolution testing used, and design of the paddles have an effect on dissolution rate, mass transfer rate, and the film thickness underlying the dissolution process.     

Choice of rotation speed (rpm) for bio-relevant drug dissolution testing using a crescent-shaped spindle.

Recently a new crescent-shaped spindle has been proposed to address the issues related to poor hydrodynamics of the USP paddle apparatus and its associated artifacts of high variability and lack of bio-relevant results. For improved comparison of drug dissolution characterization, it is highly desirable to conduct testing using common experimental conditions such as spindle rotation speed. A study was conducted in which different products were tested using the crescent-shaped spindle to propose a common rpm speed for improved comparative drug dissolution testing. Conventional- (200 mg) and extended-release (200 and 400 mg) carbamazepine tablets of multiple brands and amoxicillin capsules (250 and 500 mg) were analysed using the crescent- shaped spindle at 25, 50 and/or 75 rpm. Drug release was evaluated for 1.5h for amoxicillin and for 3.0 and 24h for conventional- and extended-release carbamazepine tablets products respectively. The dissolution media used were 0.05 M phosphate buffer for amoxicillin capsules and water containing 0.5% sodium lauryl sulphate for carbamazepine tablet products. All products showed characteristic drug release profiles, reflecting the fast and slow drug release natures of the products tested with complete drug release within expected time durations. Based on an expected maximum drug release criterion of 85% in a reasonable time, at a relatively slow drug release rate and within a dosing interval, a spindle speed of 25 rpm was found to be the most appropriate. Thus, it is concluded that drug products can be analysed using a single spindle type (crescent) with a single rpm (25) which would, not only result in simpler dissolution procedures, but also provide enhanced efficiencies from economical and regulatory aspects.     

Predictive Ability of Level A in Vitro-in Vivo Correlation for RingCap Controlled-Release Acetaminophen Tablets

Purpose. The goal of this study was to establish and validate an in vitro-in vivo correlation (IVIVC) for two sustained-release formulations (i.e., a matrix tablet and a RingCap banded matrix tablet) containing 750 mg of acetaminophen. Methods. The in vitro dissolution and in vivo disposition of these formulations were examined by using a USP type III dissolution apparatus and a single-dose, three-way, crossover study that included an immediate-release acetaminophen dosage form, respectively. An IVIVC was established by using the mean fraction dissolved (FD) and mean fraction absorbed (FA) and used to simulate the plasma concentation-time profile of acetaminophen after administration of the matrix tablet (i.e., internal validation) and RingCap banded matrix tablet (i.e., external validation). Results. A statistically significant relationship (r ² = 0.997, P < 0.001) existed between the FD and FA for matrix tablets and was best described by the equation (FA) = 0.984 × (FD) + 0.0133. The percent predictions errors in CMAX and AUCL were <10% when predicting the plasma concentration-time profiles for the two formulations, validating the internal and external predictability of the IVIVC. Conclusions. The data (i) show that in vitro dissolution data are a good predictor of in vivo fraction absorbed for acetaminophen, (ii) support the general use of in vitro dissolution data for readily soluble and readily absorbed drugs, (iii) suggest that acetaminophen may serve as a model drug for evaluating novel sustained-release delivery systems, and (iv) provide a tangible example of the limitations of current methods for predicting and validating IVIVC.