Mean Dissolution Time Research Articles

Impact of Tablet Shape on Drug Dissolution Rate Through Immediate Released Tablets.

Purpose: The aim of this study was to evaluate the influence of the geometric shape on the dissolution rate of the domperidone, a drug model for immediate release dosage form. In this regard, a lack of sufficient information about the effective dissolution rate of the drugs regarding their shapes has made this issue an interesting subject for researchers. Methods: For this purpose, three tablet shapes, namely flat and biconvex both in a round and oblong shapes, with different four sizes were modelled for the preparation of domperidone tablet. In vitro dissolution test was accomplished using a USP dissolution apparatus II. The drug dissolution rate was assessed by calculating various dissolution parameters; e.g., dissolution efficiency (DE), mean dissolution rate (MDR), mean dissolution time (MDT), and difference and similarity factors (f1 and f2 ). Results: Regarding the disintegration time, the larger tablets showed a faster disintegration time. When the size of the tablets was smaller, the amount of released drug was significantly decreased. In addition, #9 tablets with a flat or biconvex geometry had obvious effects on the DE values. Generally, biconvex tablets had higher DE percentage than the flat tablets. Conclusion: Noticeable differences in dissolution parameters by considering the different geometric shapes play an important role in the drug release kinetics which makes a significant effect on quick onset of action in oral administration.

Enhancing the Hypolipidemic Effect of Simvastatin in Poloxamer-Induced Hyperlipidemic Rats via Liquisolid Approach: Pharmacokinetic and Pharmacodynamic Evaluation.

This study aimed to enhance the dissolution of simvastatin (SMV) through its formulation in liquisolid tablets (LSTs) to improve its bioavailability and hypolipidemic activity after oral administration. SMV-LSTs were optimized using Box-Behnken design to maximize the rate and extent of SMV dissolution. The optimized SMV-LST was evaluated for pharmacokinetic parameters and potential hypolipidemic activity on induced hyperlipidemic rats. The dissolution parameters revealed a shortening of mean dissolution time from 10.99 to 6.82min, increasing of dissolution rate during the first 10min from 1253.15 to 1667.31μg/min, and enhancing of dissolution efficiency after 60min from 71.92 to 86.93% for SMV-LSTs versus the commercial SMV tablets. The obtained data reflected an improvement in the relative bioavailability of SMV with 148.232% which was confirmed by the significant reduction of the levels of circulating total cholesterol, triglycerides that reached the normal level after 12h. In particular, the optimized SMV-LSTs reduced serum low-density lipoproteins (LDL) by 44.6% which was significantly different from the commercial SMV tablets. In contrast, the level of serum high-density lipoprotein (HDL) was significantly augmented after 4h in rats treated with the optimized SMV-LSTs by 47.6%. Finally, the optimized SMV-LSTs showed a significant lower atherosclerotic index value which could maximize its potential in decreasing the risk of coronary disease and atherosclerosis. Overall enhancement in pharmacokinetics and pharmacodynamics in comparison with the commercial tablets confers the potential of the liquisolid approach as a promising alternative for improved oral bioavailability, hypolipidemic, and cardioprotective effects of SMV. Graphical abstract.

A Design of Experiment Approach for Optimization and Characterization of Clarithromycin Ternary System Using Spray Drying

The aim of present work was to characterize Clarithromycin (CLT), Polyvinyl pyrrolidone K30 (PVP K30) and Hydroxypropyl β-cyclodextrin (HPB) ternary system so as to check the effect of complexation on solubility of CLT. Physical mixtures of a drug and polymers in several weight ratios (1:1, 1:2) were prepared to check the effect of individual polymers on solubility of CLT. Spray drying method was accustomed investigate the combined effect of PVP K30 and HPB on Drug release (DR), Dissolution efficiency (DE) and mean dissolution time (MDT) of CLT. For the preparation and optimization of ternary system the Design of experiment (DoE) was used . Drug polymer interactions were analyzed with Fourier transform infrared spectroscopy (FTIR), Differential scanning calorimetry (DSC), X-ray diffraction (XRD) and particle size analysis. Results of solubility study suggested that there was significant increase in solubility of CLT with increase within the concentration of PVP K30 and HPB (*p<0.05). This may be thanks to the solubilizing effect of PVP K30 and sophisticated formation of CLT with HPB. Various combinations of PVP K30 and HPB prepared using DoE approach by spray drying method showed greater solubility of CLT than its physical mixtures (*p<0.05). Results of FTIR, DSC, XRD and particle size analysis revealed the interaction between CLT, PVP K30 and HPB. This suggested formation of amorphous ternary system with mean particle diameter within the range of 312±1.35 nm. Combine use of PVP K30 and HPB with DoE approach was an efficient tool for formulating ternary system of CLT.
 Keywords: Clarithromycin, Spray drying, polyvinyl pyrrolidone K30, Hydroxypropyl β-cyclodextrin, Design of experiments, Ternary system.

Design and evaluation of sustained release hydrophilic matrix tablets of Piroxicam based on carboxymethyl xanthan derivatives

ABSTRACT The objective of this study was to formulate hydrophilic matrices for a controlled delivery of Piroxicam using carboxymethyl xanthan gum derivatives (CMX). CMXs with various degrees of substitution (DS = 0.22, 1.70 and 2.85) were synthesized by an etherification reaction, and their characterization was realized by FT-IR spectroscopy, X-ray diffraction, and scanning electron microscopy. Different tablets were prepared using the direct compression method. The powder mixtures were characterized by the determination of their angle of repose, compressibility index and Hausner ratio, whereas weight uniformity, hardness, friability, drug content, and in-vitro drug dissolution were employed to test the tablets under simulated gastric and intestinal conditions. The obtained results indicated that the drug release rate increases with the CMX ratio. The matrices based on CMX2 (DS = 1.7) were found to be the best candidates in controlling the release profile, where the optimal formulation contains 40% of CMX2 (F9). The dissolution data showed that all matrices fit well with Korsmeyer–Peppas model, whereas the release kinetics of F9 followed non-Fickian type release. The highest mean dissolution time value was obtained for F9. Finally, these results revealed that CMXs are suitable excipients for the sustained release dosage forms for as long as 20 h.

In vitro release studies of furosemide reference tablets: influence of agitation rate, USP apparatus, and dissolution media.

Furosemide is a diuretic drug widely used in chronic renal failure. The drug has low solubility and permeability, which cause clinical problems. Studying the in vitro release performance elucidates the rate and extent of drug dissolved from dosage forms under different conditions. Furosemide reference tablets were tested using USP Apparatuses 1 and 2 as well as the flow-through cell method (USP Apparatus 4), a dissolution apparatus that simulates the human gastrointestinal tract better than the other methods. Dissolution profiles were created with USP Apparatuses 1 and 2 at 25, 50, and 75 rpm and 900 mL of 0.1 M hydrochloric acid, acetate buffer (pH 4.5), and phosphate buffer (pH 6.8). USP Apparatus 4 with a laminar flow of 16 mL/min and 22.6 mm cells was used. Drug dissolution was quantified at 274 nm for 60 min. Mean dissolution time, dissolution efficiency, time to 50% dissolution, and time to 80% dissolution data were used to compare dissolution profiles. Additionally, zero-order, first-order, Higuchi, Hixson-Crowell, Makoid-Banakar, and Weibull models were used to adjust furosemide dissolution data. Between USP Apparatus 1 and 2, significant differences were observed in almost all parameters at 50 and 75 rpm (p < 0.05). A similar dissolution profile (f2 > 50) with a pharmacopoeial dissolution method (USP Apparatus 2 at 50 rpm and 900 mL of phosphate buffer pH 5.8) and USP Apparatus 4 (laminar flow of 16 mL/min, 22.6 mm cells, and pH 6.8) was observed. The Weibull function was the best mathematical model to describe the in vitro release performance of furosemide in the three USP dissolution apparatuses. These results could be used to manufacture better furosemide dosage forms and decrease the negative clinical impact of current furosemide formulations.

Topical gel with ethyl cellulose based microsponges loaded with clindamycin hydrochloride for acne treatment

This study describes development of a dosage form for acne treatment. A topical semi-solid dosage form—gel with clindamycin-hydrochloride (CM-HCl) loaded ethyl cellulose based microsponges (MSP). Central composite experimental design was used for optimization of the formulation in means of particle size and drug loading. CM-HCl MSP optimal formulation was prepared and characterized in aspect of: particle size (D50-14.9 μm) and particle size distribution (Span-1.979); shape (spherical) and morphology (porous); FTIR spectra; drug content (CM-HCl/polymer (mg/mg)-1.2544) and drug release with mean dissolution time (MDT) of 4.51 h. Chitosan (2%) was used as a gelling agent for the optimal sample formulation. The gel showed pseudoplastic behavior and high value of spreading capacity (263.64% spreading after 5 min). It was translucent without presence of foreign particles and had typical light-yellow colour, pH value of 5.36 ± 0.15 and MDT of 7.17 h. Stability studies performed at 25° ± 2 °C/60% ± 5% RH and 40° ± 2 °C/75% ± 5% RH for a period of 6 months were in favor of the stability of the designed topical semi-solid dosage form.

Chewable Antacid Tablets: Are Disintegration Tests Relevant?

A recently published FDA guidance on chewable tablets has addressed the quality attributes of this class of dosage forms. This study evaluated disintegration as a quality attribute for a number of commercially available chewable antacid tablets. Additionally, acid-neutralizing-capacity values were evaluated. A number of the products exhibited prolonged disintegration times-which were far longer than those of conventional immediate-release tablets. The mean disintegration times ranged from 6 to more than 60min in distilled water and from 9 to over 60min in 0.1N HCl. The products with longer disintegration times had higher breaking force and tensile strength values. Despite the range in disintegration times, all products met the criteria for acid-neutralizing capacity. These results indicate a need for patients to be aware of the need to thoroughly chew antacid tablets upon administration. Given these considerations, disintegration testing would be a useful quality control test in evaluating these dosage forms as the implicit assumption by the manufacturer that patients will chew the product sufficiently may not be met in every case.

Comparative In Vitro and In Vivo Evaluation of Fenofibric Acid as an Antihyperlipidemic Drug.

Fenofibric acid (FA) is antihyperlipidemic agent and commercially available as a tablet formulation that weighs 840 mg for 105 mg of active substance. A new formulation with less inactive substance was developed as an alternative to the conventional formulation. The purpose of this study was to evaluate the dissolution and the relative bioavailability of the surface solid dispersion (SSD) and conventional formulations of FA by comparing them with the reference formulation in its commercial tablets. The in vitro-in vivo correlation among these tablet formulations was also evaluated. The dissolution study was performed in phosphate buffer pH 6.8 and biorelevant fasted state simulated intestinal fluid. Dissolution efficiency and mean dissolution time (MDT) were used to compare the dissolution profiles. The bioavailability study, using nine healthy volunteers, was conducted based on a single-dose, fasted, randomized, crossover design. The in vivo performance was compared using the pharmacokinetic parameters Cmax, Tmax, AUC0-72, and AUC0-∞. A linear correlation model was tested using MDT and mean residence time (MRT). The results indicated that there were significant differences in the dissolution performances but no significant differences among the mean Cmax, Tmax, AUC0-72, or AUC0-∞ estimated from the SSD, conventional, and reference formulations. A poor correlation was found between MRT and MDT of the three formulations. The SSD formulation led to an instantaneous dissolution of the drug due to the presence of the polymer and the physical structure of the SSD. The conventional formulation could not achieve rapid dissolution despite its satisfying the requirement for immediate drug release dosage form. Both formulations could be considered bioequivalent with the reference. The in vitro dissolution behavior of FA using a single medium did not reflect their in vivo properties in the fasted condition. There was no correlation between the in vitro dissolution and the in vivo bioavailability of FA in this condition.

An Optimized Surfactant-Based PEG-PLCL In Situ Gel Formulation For Enhanced Activity Of Rosuvastatin In Poloxamer-Induced Hyperlipidemic Rats.

BackgroundInjectable in situ gel (ISG) systems suffer from high initial drug release that may result in toxic effects.ObjectiveThis work aimed to develop an injectable sustained release rosuvastatin (RSV) ISG formulation with minimum initial drug burst and improved hyperlipidemic efficacy.MethodsSix formulation factors that affect RSV release after 0.5, 2 and 24 hrs have been screened and the significant ones were optimized utilizing an experimental design tool. The optimum ISG formulation components were physicochemically characterized. Kinetic treatment, dissolution efficiency and mean dissolution time were investigated for the developed ISG formulations. Pharmacodynamic effects of the optimized ISG formulation were studied and compared to ISG formulation loaded with free RSV and to a marketed oral drug product.ResultsThe concentration polylactide-co-ε-caprolactone (25: 75), the surfactant hydrophilic lipophilic balance (HLB) and the ratio of surfactant to polyethylene glycol 400 were significantly affecting the release of RSV during the first 24 h. Physicochemical characterization demonstrated complete dispersion of RSV in the polymeric matrix with slight changes in the drug crystalline structure. The optimized formulation demonstrated acceptable syringeability, good flow rate and was able to extend the in vitro drug release for 34 days. The ISG formulations complied with Weibull model. Pharmacodynamic study revealed a sustained reduction in the lipid profile that lasted for 21 days with a marked decrease in the lipid level during the first 24 hrs from the ISG system loaded with free RSV.ConclusionThe optimized RSV ISG formulation could be considered a promising strategy due to a reduction in dosing frequency and enhancement in hypolipidemic efficacy.

STATISTICAL INTERPRETATION AND OPTIMIZATION OF VALSARTAN FLOATING TABLETS USING BOX-BEHNKEN DESIGN

Objective: The main purpose of this study was to formulate and statistically evaluate 300 mg floating tablets of valsartan.&#x0D; Methods: Floating tablets of valsartan was prepared in 16 station rotary punching machine by considering 300 mg of valsartan as drug, 40-60 mg of hydroxypropyl methylcellulose (HPMC) K100M and 20-40 mg of poly (styrene-divinylbenzene) as polymers and 20 mg of sodium bicarbonate as gas generating agents. Since upper stomach has maximum therapeutic window for valsartan absorption, hence Gastroretentive Floating Tablets (GRFTs) was prepared by implementing Box-Bentham Design. The pre and post compression parameters were optimized using Statistica 10 software. From the in vitro buoyancy and drug release studies and interpretation of statistical outcomes viz. Akaike Information Criterion (AIC), Bayesian Information Criterion (BIC), Root Mean Squared Error (RMSE), Dissolution Efficiency (DE), Mean Dissolution Time (MDT), desirability study, it was concluded that batch VF5 formulation was found to be the most optimized formulation.&#x0D; Results: The floating time of VF5 was found to be 132±0.33 sec, in vitro buoyancy time was 18 h, Akaike Information Criterion (AIC) was 54.97, Bayesian Information Criterion (BIC) was 5.13, percentage dissolution efficacy was 56.39%, mean dissolution time was 5.19hr. Further, six-month stability study was performed as per ICH QIA guideline. After performing two-way ANOVA within stability study response variables, it was confirmed that the interaction was most significant.&#x0D; Conclusion: Valsartan floating drug delivery system was successfully developed by considering HPMC K100M and poly (styrene-divinylbenzene) as polymers. Among all the nine batches, VF5 was found to be the best-optimized batch.

IN VITRO EQUIVALENCE STUDY OF DIFFERENT DOSES OF CARBAMAZEPINE REFERENCE TABLETS USING USP APPARATUSES 2 AND 4

Objective: To perform an in vitro equivalence study of two doses of carbamazepine reference tablets sold in the local market under hydrodynamic conditions of USP Apparatus 4, a dissolution apparatus that better simulates the human gastrointestinal tract. Results were compared with dissolution official conditions using USP Apparatus 2.&#x0D; Methods: Dissolution profiles of both formulations were carried out with an automated USP Apparatus 2 at 75 rpm and 900 ml of dissolution medium. USP Apparatus 4 with laminar flow at 16 ml/min and 22.6 mm cells were used. 1% lauryl sulfate aqueous solution at 37.0±0.5 °C was used as dissolution medium. Spectrophotometric determination of drug at 285 nm was carried out during 60 min. Dissolution profiles were compared with model-independent and-dependent approaches.&#x0D; Results: When comparing dissolution profiles of low vs. high dose similar profiles were found (f2&gt;50) in each dissolution apparatus, however, when the same dose was compared, USP 2 vs. USP 4, opposite results were obtained. Comparison of mean dissolution time and dissolution efficiency data corroborates these results. Weibull function was the best mathematical model that described the in vitro dissolution performance of carbamazepine. No significant differences were found in Td values (low vs. high dose) but opposite results were also found with USP 2 vs. USP 4.&#x0D; Conclusion: Equivalent dissolution performance of two doses of carbamazepine reference tablets were found in each USP dissolution apparatus. The main problem identified in this comparative study is the low dissolution rate and extent found with USP Apparatus 4. More research on this field is necessary for all available doses of reference drug products since the quality of generic formulations depends on the quality of references.

DISSOLUTION PERFORMANCE OF MELOXICAM FORMULATIONS UNDER HYDRODYNAMICS OF USP PADDLE APPARATUS AND FLOW-THROUGH CELL METHOD

Objective: To study the in vitro dissolution performance of four generic formulations of the poorly soluble drug meloxicam and the reference under hydrodynamic environments generated by flow-through cell method and USP paddle apparatus (pharmacopeial test).&#x0D; Methods: Dissolution method was validated according to ICH guidelines. Dissolution profiles were carried out with an automated flow-through cell apparatus (laminar flow at 16 ml/min with 22.6 mm cells) and USP paddle apparatus at 75 rpm. Phosphate buffer pH 7.5 at 37.0±0.5 °C was used as dissolution medium. Spectrophotometric determination of drug at 362 nm was carried out during 30 min. Dissolution profiles were compared with model-dependent and-independent methods.&#x0D; Results: Practically, all generic formulations showed significant differences with the percentage of drug dissolved at 30 min, mean dissolution time and dissolution efficiency, when USP paddle apparatus was used (*P&lt;0.05), while only two generic formulations were different to reference using flow-through cell method. After adjustment to different mathematical equations, Weibull function was the best model to describe meloxicam dissolution performance and significant differences were found with all drug products when USP paddle apparatus was used, while only one formulation was different with flow-through cell method.&#x0D; Conclusion: The study reveals the need to look for better dissolution schemes for meloxicam tablets since USP paddle apparatus may not reflect properly the in vitro dissolution performance of meloxicam generic formulations and reference.

INFLUENCE OF DOSE AND USP DISSOLUTION APPARATUS IN THE RELEASE PERFORMANCE OF REFERENCE TABLETS: PROPRANOLOL-HCl AND RANITIDINE-HCl CASES

Objective: Due to quality of generic formulations depends on available information of reference drug products the aim of this work was to perform an in vitro dissolution study of two doses of propranolol-HCl and ranitidine-HCl reference tablets using USP basket or paddle apparatus and flow-through cell method.&#x0D; Methods: Two doses of propranolol-HCl (10-mg and 80-mg) and ranitidine-HCl (150-mg and 300-mg) of Mexican reference products were used. Dissolution profiles of propranolol-HCl were obtained with USP basket apparatus at 100 rpm and 1000 ml of 1% hydrochloric acid. Profiles of ranitidine-HCl were determined with USP paddle apparatus at 50 rpm and 900 ml of distilled water. All formulations were also studied with the flow-through cell method using laminar flow at 16 ml/min. Dissolution profiles were compared by model-independent (f2 similarity factor, mean dissolution time and dissolution efficiency) and model-dependent methods (dissolution data adjusted to some mathematical equations). Time data, derived from these adjustments, as t50%, t63.25%, and t85% were used to compare dissolution profiles.&#x0D; Results: With all approaches used and being high solubility drugs significant differences were found between low and high doses and between USP dissolution apparatuses (*P&lt;0.05).&#x0D; Conclusion: In vitro dissolution performance of two doses of propranolol-HCl and ranitidine-HCl was not expected. Considering the same USP dissolution apparatus, the reference tablets did not allow the simultaneous release of the used doses. The results could be of interest for pharmaceutical laboratories or health authorities that classify some drug products as a reference to be used in dissolution and bioequivalence studies.

Films based on the biopolymer poly(3-hydroxybutyrate) as platforms for the controlled release of dexamethasone

Controlled drug delivery aims to achieve an effective drug concentration in the action site for a desired period of time, while minimizing side effects. In this contribution, biodegradable poly(3-hydroxybutyrate) films were evaluated as a reservoir platform for dexamethasone controlled release. These systems were morphological and physicochemically characterized. In vitro release assays were performed for five different percentages of drug in the films and data were fitted by a mathematical model developed and validated by our research group. When the profiles were normalized, a single curve properly fitted all the experimental data. Using this unique curve, the dissolution efficiency (DE), the time to release a given amount of drug (tX%), and the mean dissolution time were calculated. Furthermore, the dissolution rate, the initial dissolution rate (a%) and the intrinsic dissolution rate were determined. The a% mean value was 1.968 × 10−2% released/min, t80% was about 14 days, and the DE was 59.6% at 14 days and 66.5% at 20 days. After 2 days, when approximately 40% of the drug was released, the dissolution rate decreased about 60% respect to the initial value. The poly(3-hydroxybutyrate) platforms behaved as an appropriate system to release and control the dexamethasone delivery, suggesting that they could be an alternative to improve drug therapy.

Mucoadhesive sustained-release tablets for vaginal delivery of Curcuma comosa extracts: Preparation and characterization

The objectives of this study were to prepare and characterize the mucoadhesive vaginal tablets of Curcuma comosa (C. comosa) extract for local delivery of the active phytoestrogens in a sustained release manner. The oleoresin-like C. comosa extract was converted into apparently dry powder by adding it into the mixture of polymer, namely polycarbophil (PCP), hydroxypropylmethylcellulose (HPMC) or the blends of PCP:HPMC, and silica. The absence of interaction between C. comosa extract and excipients was confirmed using FTIR. C. comosa mucoadhesive powder was directly compressed into 24-mm capsule shape tablets. All prepared tablets had acceptable physical properties and uniformity of diarylheptanoids (DAs), namely (3R)-1,7-diphenyl-(4E,6E)-4,6-heptadien-3-ol (DA1) and (3S)-1,7-diphenyl-(6E)-4,6-hepten-3-ol (DA2). Blending PCP with HPMC could improve swelling and mucoadhesive properties of the tablets (p < 0.05). In vitro release showed that DAs were released over a period of 72 h in a sustained manner. The almost complete DA release was found in the formulation prepared with HPMC, of which the mean dissolution time of DA1 and DA2 stood at 34.7 ± 4.1 and 32.1 ± 3.7 h, respectively. Stability study reveals that C. comosa tablets were stable in terms of tablet properties, DA content and release characteristics when stored in a refrigerator.

Enhancement of Dissolution of Fenofibrate Using Complexation with Hydroxy Propyl β-Cyclodextrin

The aim of the present study was to enhance the dissolution rate of fenofibrate using complexation with hydroxy propyl β-cyclodextrin (HPβCD). The phase solubility behavior of fenofibrate was studied in various concentrations of (HPβCD) aq. solution at 37°C. The solubility of fenofibrate increased with an increase in the amount of HPβCD aq. solution. Gibbs free energy (ΔG°)tr values were all negative. Complexes of fenofibrate with HPβCD were prepared in 1:1 ratio by kneading and coprecipitation. These complexes were evaluated by dissolution studies, fourier transform infrared (FTIR) spectroscopy, and differential scanning calorimetry (DSC) studies. The complexation of fenofibrate with HPβCD exhibited an enhanced dissolution rate. The mean dissolution time of fenofibrate decreased significantly upon complexation. FTIR studies showed the formation of intermolecular hydrogen bonding between fenofibrate and HPβCD. DSC studies indicated a loss in crystalline state of fenofibrate in complexes. Complexation with HPβCD can be used as a useful tool for the enhancement of dissolution of fenofibrate.

Combined Application of MRI and the Salivary Tracer Technique to Determine the in Vivo Disintegration Time of Immediate Release Formulation Administered to Healthy, Fasted Subjects.

The process of disintegration is a crucial step in oral drug delivery with immediate release dosage forms. In this work, the salivary tracer technique was applied as a simple and inexpensive method for the investigation of the in vivo disintegration time of hard gelatin capsules filled with caffeine. The disintegration times observed with the salivary tracer technique were verified by magnetic resonance imaging (MRI). After an overnight fast of at least 10 h and caffeine abstinence of minimum 72 h, conventional hard gelatin capsules containing 50 mg caffeine and 5 mg iron oxide were administered to 8 healthy volunteers. For the period of 1 h after capsule intake, subjects were placed in supine position in the MRI scanner, and scans were performed in short time intervals. Each MRI measurement was directly followed by saliva sampling by drooling. Salivary caffeine concentrations were determined by high performance liquid chromatography followed by mass spectrometric detection (LC/MS-MS). The time point of capsule disintegration was determined by visual inspection of the MR images as well as by an increase in the salivary caffeine concentration. The results indicated that the difference in mean disintegration times of the capsules as determined by the two in vivo methods was around 4 min (8.8 min for MRI vs 12.5 min for saliva). All disintegration times determined by the salivary tracer technique were slightly higher. This delay could be explained by the fact that the appearance of caffeine in saliva required drug absorption in the small intestine. Because capsule disintegration happened mainly in the stomach, the exact site of disintegration as well as the processes of gastric mixing and gastric emptying contributed to the delay between the two methods. This work demonstrated the feasibility of the salivary tracer technique to investigate the in vivo disintegration of immediate release dosage forms in a simple and reliable manner.

Dissolution testing of oral film preparations: Experimental comparison of compendial and non-compendial methods

In vitro dissolution testing is one of the most frequently used tests in pharmaceutical quality control, since evaluation of the drug release profile and estimation of the dosage form performance is enabled. However, for oral film preparations no standardized compendial dissolution method or specifications are available worldwide.Therefore, four different dissolution methods described in the literature, namely the basket method, the paddle and glass disc (PGD) method, the flow-through cell with adapted film sample holders produced via 3D printing (FTC + FH3D) and the “Punch and Filter” (PAF) method were chosen and their suitability to investigate oral films with different release properties was compared. For this purpose, oral films with immediate (ODFIR) and prolonged theophylline release (ODFPR) as well as double layer films (ODFDL) were produced and investigated.All produced ODFs disintegrated rapidly in 27–46 s and showed content uniformity with acceptance values between 7.3 and 11.3%. The FTC + FH3D and the PGD method showed increased discriminatory power and were suitable to investigate the integrity of the shielding layer of ODFDL as shown by linear prolonged release (mean dissolution time at 80% drug release (MDT80) of 366.8 and 217.1 min for FTC + FH3D and PGD method), which was not possible applying the basket and PAF method. These methods did not allow clear discrimination between ODFIR and ODFDL, since immediate release profiles with MDT80 values of 4.1 and 11.0 min for the basket method and 6.8 and 15.5 min for the PAF method were found for both, ODFIR and ODFDL respectively. The FTC + FH3D method provided high flexibility, which may be used to simulate gastrointestinal transit. The PAF method reflects physiological conditions of the oral cavity and enables mimicking the in vivo film application. These methods are particularly valuable for research and development purposes. Due to the simple and well standardized instrumental setup as well as high robustness, the basket and PGD method are particularly suitable for use in pharmaceutical quality control.

Characterization of the gastrointestinal transit and disintegration behavior of floating and sinking acid-resistant capsules using a novel MRI labeling technique

The application areas of hard capsules are currently widened by the introduction of acid-resistant capsule shells. In this study, the gastrointestinal behavior of acid-resistant hard capsule formulations as well as the influence of their density on the gastric residence time were characterized using magnetic resonance imaging (MRI). As labeling material for a reliable identification of the capsules in the MR images, small pieces of dried pineapple were used as they provide a high T1 signal. Tested products were DRcaps™ as capsule in capsule (Cap-in-Cap) system (outer capsule size 00). For the investigation of the influence of the capsule density on the gastric residence time, a floating low-density Cap-in-Cap capsule formulation and a sinking high-density Cap-in-Cap capsule formulation were investigated. The study was performed in eight healthy human subjects under fasting conditions. Besides the transit data of the capsule systems, the intraluminal fluid volume kinetics were determined using T2 weighted sequences.The gastric emptying times of the systems did not differ, with mean values of 45 ± 35 min for floating DRcaps™ and 36 ± 18 min for the sinking DRcaps™. The difference in density had no remarkable influence on gastric emptying. Thus, the concept of floating capabilities for gastroretentive dosage forms seems rather implausible. Furthermore, this assures transferability of common knowledge about dosage form transit for estimation of the performance of acid-resistant capsule shells, which most typically float. The mean disintegration times amounted to 139 ± 35 min for the floating DRcaps™ Cap-in-Cap and 163 ± 55 min for the sinking DRcaps™ Cap-in-Cap. In only one case, a sinking DRcaps™ Cap-in-Cap system disintegrated during gastric emptying, but all other capsules disintegrated in the small intestine, irrespective of their gastric residence time. The use of dried pineapple as labeling material could be successfully demonstrated as a reliable and easy method for the tracking of the transit and disintegration behavior of orally administered drug delivery systems, leading to a thorough understanding of their in vivo performance.

A spray dried Nelfinavir Mesylate particles for enhanced oral bioavailability: Systematic formulation optimization and in-vivo performance.

The current endeavor was aimed to fabricate spray dried Nelfinavir Mesylate particles (SDNPs) that upon reconstitution with body fluids releases amorphous Nelfinavir Mesylate with enhanced oral bioavailability. For this purpose, feed mixture was prepared containing solubilized NFM, solid substrate and solvent system. The NFM was solubilized in a mixture of Maisine 35-1 (200 mg), Tween80 (500 mg) and Transcutol HP (300 mg). Three different solid substrates with high specific surface area were used: Neusilin® UFL2, (magnesium aluminometasilicate), Aerosil 200® (colloidal silica) and Syloid 244 FP® (porous silicon dioxide). Central composite design-response surface methodology (CCD-RSM) with three-factor (two numeric and one categorical) at three-level was used to select the appropriate solid substrate and to develop optimized SDNPs. The solid characterization by scanning electron microscopy, differential scanning calorimetry and powder X-ray diffraction studies indicated the absence of crystalline NFM in the formulations. The drug distribution analysis using raman spectroscopy suggested uniform distribution of amorphous NFM in optimized SDNPs-1 formulation. The transmission electron microscopy revealed the spherical structure of reconstituted SDNPs that releases amorphous NFM with globules size less than 110 nm. The solid substrate had significant and positive effect in drug dissolution; the mean dissolution time of NFM loaded in SDNPs was considerably improved. The bioavailability study resulted in enhanced magnitude of Cmax and AUC for SDNPs. The tissue distribution studies exhibited significantly higher brain and lymph nodes distribution as compared to putative form. Overall, the results pointed towards the overwhelming response of the SDNPs to be used for HIV treatment.