Drug Dissolution Profiles Research Articles

Liquigroud technique: a new concept for enhancing dissolution rate of glibenclamide by combination of liquisolid and co-grinding technologies.

Introduction: The potential of combining liquisolid and co-grinding technologies (liquiground technique) was investigated to improve the dissolution rate of a water-insoluble agent (glibenclamide) with formulation-dependent bioavailability. Methods: To this end, different formulations of liquisolid tablets with a wide variety of non-volatile solvents contained varied ratios of drug: solvent and dissimilar carriers were prepared, and then their release profiles were evaluated. Furthermore, the effect of size reduction by ball milling on the dissolution behavior of glibenclamide from liquisolid tablets was investigated. Any interaction between the drug and the excipient or crystallinity changes during formulation procedure was also examined using X-ray diffraction (XRD) and differential scanning calorimetry (DSC). Results: The present study revealed that classic liquisolid technique did not significantly affect the drug dissolution profile as compared to the conventional tablets. Size reduction obtained by co-grinding of liquid medication was more effective than the implementation of liquisolid technique in enhancing the dissolution rate of glibenclamide. The XRD and DSC data displayed no formation of complex or any crystallinity changes in both formulations. Conclusion: An enhanced dissolution rate of glibenclamide is achievable through the combination of liquisolid and co-grinding technologies.

In Vitro - In Vivo Evaluation Of E/R Trilayer Matrix Tablets Containing Solid Dispersion Of Atorvastatin

<p>Investigation of <em>in vitro/in vivo</em> behaviour of extended release tablets containing solid dispersions of Atorvastatin is the focus of the present research work. Atorvastatin trilayer matrix tablets were prepared by direct compression method and consisted of middle active layer with different grades of hydroxypropylmethylcellulose (HPMC), ethyl cellulose and Carbopol 934P. Barrier layers are prepared with hydrophobic polymers carnauba wax and xanthan gum. Based on the evaluation parameters, drug dissolution profile and release order kinetics HF16 was found to be optimized formulation. The developed drug delivery system provided prolonged drug release rates over a period of 24 h. The release profile of the optimized formulation (HF16) was described by the Zero-order and best fitted to Higuchi model. FTIR confirmed that there was no chemical interaction between drug and excipients used in the formulation. . In vivo bioavailability studies were conducted for optimized formulation HF16 and reference standard. The optimized formulation of Atorvastatin trilayer matrix tablet was shown significant plasma concentration with extended release and maintained for 24 hrs with patient compliance by reducing the dosage frequency, when compared with reference standard. </p>

The performance of HPMC matrix tablets using various agglomeration manufacturing processes

Context: The flow and compaction properties of a compaction mixture or powder and the drug-release profile of final tablets are important critical quality attributes (CQAs) that have an impact on the overall performance of hydrophilic matrix tablets. The selection of granulation method can importantly affect these CQAs.Objective: This study investigates various agglomeration methods of sustained-release formulation using HPMC K4M as a release polymer with various wet- and dry-granulation techniques.Materials and methods: Flow properties were determined using flow time, angle of response, and the Carr index. Compaction properties were evaluated using “out of die” Heckel model. Release of carvedilol was tested as 12-h drug-dissolution profile.Results and conclusion: Compression mixtures made using the wet-granulation method exhibit better flow and compression properties than compression mixtures made using the dry-granulation method. The direct compression method proved to be the least appropriate manufacturing method because the compression mixture has very poor flow and the lowest compressibility/compactibility index. The choice of granulation technique significantly influences the swelling behavior and drug-dissolution profile of the final matrix tablets, also resulting in dissimilar release profiles. The choice of granulation method has the greatest influence on the drug-release profile. The direct compression method provides tablets with the fastest drug-release profile, followed by the dry-granulation and wet-granulation methods. The particle size of granules and porosity of tablets play an important role, contributing to differences in drug-release profiles.

КОМПЛЕКСНІ ДОСЛІДЖЕННЯ ЕКВІВАЛЕНТНОСТІ IN VITRO КАПСУЛ МЕЛЬДОНІЮ

В статті наведено результати комплексу досліджень за процедурою біовейвер щодо встановлення біоеквівалентності досліджуваних та референтних лікарських засобів мельдонію в формі твердих капсул по 250 мг та 500 мг. За результатами вивчення розчинності і ступеня проникнення встановлено І клас за БОК для діючої речовини мельдоній. Визначено, що об'єкти дослідження належать до дуже швидко розчинних лікарських засобів у всіх рекомендованих середовищах розчинення. Подібність профілів розчинення свідчить про еквівалентність досліджуваних та референтних лікарських засобів мельдонію

Influence of dissolution-modifying excipients in various pharmaceutical formulations on electronic tongue results

The overall performance of a potentiometric electronic tongue (ET) as well as the sensitivity and selectivity pattern of particular ion-selective electrodes forming the array towards exemplary APIs (metamizole sodium, pseudoephedrine sulphate) and excipients (hypromellose, carmellose, Eudragit E) was determined. Simultaneous sensing of both API and the encapsulating excipient in their physical mixture was noticed using potentiometric sensors. Usually, such altering of chemical image is treated as an evidence of taste masking/modified release effect (linked with chemical entrapment of API in polymer matrix), while the observed “mixture effect” can also take place which may complicate the interpretation of ET results. Moreover, the influence of the same excipients on chemical images of various APIs was compared and related to sensor array performance. The presented considerations should be taken into account in the case of ET assessment of drug dissolution profiles and detection of modified release effect, especially when novel drug delivery systems are considered.

Stability analysis and quantitative evaluation of metronidazole suspension

Suspension is a heterogeneous mixture including solid particles that are satisfactorily bulky for sedimentation. Generally they must be larger than one micrometer. It is when particles are left floating around freely in a solvent. The inner phase (solid) is discrete all through the external phase (fluid) during mechanical stir, with utilizing of certain excipients or suspending agents. Metronidazole or 2-(2 methyl-5 nitro-1 H –imidazol-1 yl) ethanol belongs to the nitro imidazole group of antibiotics whose antimicrobial property through derive from the formation of toxic free radicals by intracellular reduction. The objective of present study was to prepare suspension of Metronidazole by using different suspending agents and stability testing was to provide evidence on how the quality of suspensions varies with the time under of influence of environmental factors such as temperature, light, oxygen, moisture, other ingredient or excipients in the dosage form, particle size of drug, microbial contamination etc. and to establish a recommended storage condition. The FTIR and DSC techniques are use for characterization of active ingredient MBZ. This suspension was evaluated for appearance, pH, sedimentation volume and dissolution study for in vitro drug release. Result of evaluation indicates 1% w/v xanthan gum give optimal characteristic suspension. Suspension containing 1% w/v was exposed for the stability studies as per ICH guidelines. The suspensions were evaluated for their physicochemical parameter, particle size, drug release, drug content and microbiological assessment. The suspension shows good stability at 25ºC ± 2 ºC /60%± 5% RH, 30 ºC ± 2 ºC /65%± 5% RH and good quantitative analysis result throughout the period of study. Suspension stored at 40 ºC ± 2 ºC /75%± 5% RH shows noncompliance with the analysis parameter after 4 week of storage. This indicate high temperature storage was shows degradation of the suspension which results in crystal growth in formulation and affect the physicochemical parameter as Appearance, pH, viscosity, specific gravity, drug dissolution profile and drug content.

Comparative study on the in vitro performance of blister molded and conventional lornoxicam immediate release liquitablets: accelerated stability study and anti-inflammatory and ulcerogenic effects

Context: Lornoxicam is a potent non-steroidal anti-inflammatory drug (NSAID). It shows limited solubility in the gastric pH, delayed bioavailability and pharmacodynamic effects with aggravated gastric side effects (due to longer residence in the stomach wall).Objective: To enhance dissolution of lornoxicam in the gastric fluid and expectedly absorption and pharmacological action, with less ulcerogenic effects.Materials and methods: Formulation of immediate release (IR) lornoxicam liquitablets containing both liquid and solid release modulators (wetting agent, solubilizers and microenvironmental pH modifiers). Beside the traditional direct compression technique employed for the preparation of liquitablets a new technique, blister molding, was also used. The effect of the two different manufacturing methods on the fast release characteristics (rapid disintegration and dissolution) was studied. Stability and pharmacological activity of the optimum formula were also explored.Results: Similarity factor pointed out the superiority of molding technique in enhancing dissolution of lornoxicam owing to significant crystallinity reduction (XRD). Optimum formula showed negligible change in drug content and dissolution profiles over 12 weeks, significantly improved anti-inflammatory activity and significantly reduced gastric ulcerative effect over pure lornoxicam and commercial formula.Discussion and conclusion: Blister molded lornoxicam liquitablet of improved dissolution and pharmacological activity and less gastric erosion was successfully prepared.

Influence of Experimental Conditions on Electronic Tongue Results-Case of Valsartan Minitablets Dissolution.

A potentiometric electronic tongue was applied to study the release of valsartan from pharmaceutical formulations, i.e., minitablets uncoated and coated with Eudragit E. Special attention was paid to evaluate the influence of medium temperature and composition, as well as to compare the performances of the sensor arrays working in various hydrodynamic conditions. The drug dissolution profiles registered with the ion-sensitive electrodes were compared with standard dissolution tests performed with USP Apparatus 2 (paddle). Moreover, the signal changes of all sensors were processed by principal component analysis to visualize the release modifications, related to the presence of the coating agent. Finally, the importance and influence of the experimental conditions on the results obtained using potentiometric sensor arrays were discussed.

Comparison of drug dissolution profiles: a proposal based on tolerance limits.

Meaningful comparison of the dissolution profiles between the reference and test formulations of a drug is critical for assessing similarity between the two formulations, and for quality control purposes. Such a dissolution profile comparison is required by regulatory authorities, and the criteria used for this include the widely used difference factor f1 and a similarity factor f2 , recommended by the Food and Drug Administration . In spite of their extensive use in practice, the two factors have been heavily criticized on various grounds; the criticisms include ignoring sampling variability and ignoring the correlations across time points while using the criteria in practice. The goal of this article is to put f1 and f2 on a firm statistical footing by developing tolerance limits for the distributions of f1 and f2 , so that both the sampling variability and the correlations over time points are taken into account. Because f1 and f2 are defined in terms of sample mean dissolution profiles, they are not appropriate for comparing individual dissolution profiles. For the latter, we have considered similar criteria and have derived tolerance limits. Both parametric and nonparametric approaches are explored, and a bootstrap calibration is used to improve accuracy of the tolerance limits. Simulated coverage probabilities show that the method leads to accurate tolerance limits. Two examples are used to illustrate the methodology. Copyright © 2016 John Wiley & Sons, Ltd.

Development of Fast Dissolving Tablets of Nisoldipine by Solid Dispersion Technology using Poloxamer 407 and Poloxamer 188

Objective: The aim of the present study is to design oral fast-release tablets of nisoldipine and to optimize the drug dissolution profile by modifying the carrier concentration. Poloxamer 407 and Poloxamer 188 were selected as carriers for preparing the solid dispersion (SD) by solvent evaporation method with different drug polymer ratios. Methods: The prepared solid dispersions were analyzed for physical state, drug:carrier interactions by Xray diffraction, infrared spectroscopy, differential scanning calorimetry and scanning electron microscopy. Results: The dissolution studies revealed that all solid dispersions showed increased dissolution rate whencompared to pure nisoldipine. Among the two polymers used, poloxamer 407(P 407) was found to be better than poloxamer 188(P 188) in the enhancement of dissolution efficiency. The tablets were formulated using solid dispersion of nisoldipine containing poloxamer 407 as carrier. Conclusion: The results exhibited that poloxamer 407 SD based tablets gave a significantly higher release of nisoldipine when compared with control tablets. Infrared spectral studies showed that there was no interaction between thenisoldipine and its formulation with different carriers used in the preparation of solid dispersions. X-ray diffraction studies revealed that the degree of crystallinity of nisoldipine decreased when the concentration of carriers increased, which showed that the drug is in amorphous nature. Key words: Fast dissolving tablets, Poloxamer 407, Poloxamer 188, Solid dispersion, Superdisintergrants.

Preparation and Optimization of Immediate Release/Sustained Release Bilayered Tablets of Loxoprofen Using Box-Behnken Design.

The aim of our current study was to characterize and optimize loxoprofen immediate release (IR)/sustained release (SR) tablet utilizing a three-factor, three-level Box-Behnken design (BBD) combined with a desirability function. The independent factors included ratio of drug in the IR layer to total drug (X 1), ratio of HPMC to drug in the SR layer (X 2), and ratio of Eudragit RL PO to drug in the SR layer (X 3). The dependent variables assessed were % drug released in distilled water at 30min (Y 1), % drug released in pH 1.2 at 2h (Y 2), and % drug released in pH 6.8 at 12h (Y 3). The responses were fitted to suitable models and statistical validation was performed using analysis of variance. In addition, response surface graphs and contour plots were constructed to determine the effects of different factor level combinations on the responses. The optimized loxoprofen IR/SR tablets were successfully prepared with the determined amounts of ingredients that showed close agreement in the predicted and experimental values of tablet characterization and drug dissolution profile. Therefore, BBD can be utilized for successful optimization of loxoprofen IR/SR tablet, which can be regarded as a suitable substitute for the current marketed formulations.

Control of Drug Dissolution Rate from Film Dosage Forms Containing Valsartan.

Film dosage forms (FDs) containing valsartan (VST), a popular antihypertensive drug, were prepared using a casting method with sodium alginate and other polysaccharides as the film base. Drug dissolution profiles of the FDs were investigated in limited medium. The FDs were 170–200 μm thick and were easy to handle. All FDs immediately swelled and disintegrated in the medium. About 23% of the VST incorporated into the FD prepared with 1.5% sodium alginate dissolved at 5 min. The initial dissolution rate of VST increased upon the addition of chitosan to the film base; this effect was not observed in the case of chitin. On the other hand, the rate apparently decreased upon modification with alginic acid. In addition, the solubility of VST in the dissolution medium was changed by the addition of chitosan or alginic acid. FDs prepared with polysaccharides are useful for simplifying the administration of drugs to patients, and the drug dissolution rate from FDs can be controlled by modification.

Development and characterization of fast-dissolving tablet formulations of glyburide based on solid self-microemulsifying systems

The aim of this work was to develop effective fast-dissolving tablet formulations of glyburide, endowed with improved dissolution and technological properties, investigating the actual effectiveness of the Solid-Self MicroEmulsifying Drug Delivery System (S-SMEDDS) approach. An initial screening aimed to determine the solubility of the drug in different oils, Surfactants and CoSurfactants allowed the selection of the most suitable components for liquid SMEDDS, whose relative amounts were defined by the construction of pseudo-ternary phase diagrams. The selected liquid SMEDDS formulations (Capyol 90 as oil, Tween 20 as Surfactant and Glycofurol or Transcutol as CoSurfactant) were converted into Solid-SMEDDS, by adsorbing them onto Neusilin (1:1 and 1:0.8w/w S-SMEDDS:carrier), and fully characterized in terms of solid state (DSC and X-ray powder diffraction), morphological (ESEM) and dissolution properties, particle size and reconstitution ability. Finally, the 1:1 S-SMEDDS containing Glycofurol as CoSurfactant, showing the best performance, was selected to prepare two final tablet formulations. The ratio test (t10 min ratio and DE60 ratio) and pair-wise procedures (difference (f1) and similarity (f2) factors) highlighted the similarity of the new developed tablets and the marked difference between their drug dissolution profiles and those of formulations based on the micronized drug. The S-SMEDDS approach allowed to develop fast-dissolving tablets of glyburide, endowed with good technological properties and able to achieve the complete drug dissolution in a time ranging from 10 to 15min, depending on the formulation composition.

Liquisolid technology applied to pellets: Evaluation of the feasibility and dissolution performance using felodipine as a model drug

This study evaluated the feasibility of liquisolid pellets as an innovative drug delivery system to improve the dissolution rate of low solubility drugs, combining the advantageous properties of multiple-unit dosage forms and the liquisolid formulations. The effects of crospovidone (Kollidon® CL-SF) as a coating and disintegrating material (4 or 8%) and the type of non-volatile solvent, PEG 400 or Cremophor® EL, on the felodipine (model drug) dissolution profile were assessed. All liquisolid formulations had increased drug dissolution rates compared to their correspondent conventional formulations. Cremophor® EL was more effective in improving the drug dissolution rate when compared to PEG 400 due to the formation of softer and more porous structures. The amount of crospovidone also showed remarkable positive effect on the drug dissolution. It was noticed a direct correlation between disintegration time and drug dissolution performance. The enhanced dissolution rates were attributed to the decrease in disintegration time of the pellets associated with the liquisolid microenvironment triggered by the non-volatile solvents. This study consists of an innovation and expansion of the current liquisolid technology since the literature did not describe so far the development of liquisolid pellets and the use of crospovidone as a coating material in liquisolid formulations.

TEMPO-oxidized Konjac glucomannan as appliance for the preparation of hard capsules

TEMPO-oxidized Konjac glucomannan (OKGM) was developed as new material for preparing vegetarian hard capsules. OKGM of different degrees of oxidation: DO30%, DO50%, and DO80% were prepared to select optimum DO for capsule formation. FT-IR results proved that the primary alcohol groups on KGM were oxidized into carboxyl groups. XRD analysis suggested that TEMPO-oxidation decreased the crystallinity of KGM. DO80% was considered as the optimum candidate for capsule preparation owing to its superior solubility, transparency and reduced viscosity. The hydrophilicity of OKGM films, measured by contact angle measurement, increased with increasing DO. The elongation at break and tensile strength of the OKGM films enhanced with increasing DO. In vitro drug dissolution profile of OKGM capsules showed that the shell rupture time of DO80% capsule is about 5–10min, and 80% of the drugs were released within 30–45min. Thus DO80% OKGM was qualified to be used for gastric soluble hard capsules.

Drug Molecule Diflunisal Forms Crystalline Inclusion Complexes with Multiple Types of Linear Polymers

Co-crystals between drug molecules and coformers have shown great potential to optimize the stability and dissolution profiles of drugs. However, most of the coformers studied so far are small molecules. Here, we use diflunisal (DIF) as the model drug, and show that it could form co-crystals with multiple types of linear polymers in the form of crystalline inclusion complexes (ICs). These drug-polymer ICs were thoroughly characterized with single-crystal and powder XRD, solid-state NMR, DSC, and TGA, and showed similar channel structures, but their thermal properties changed with the type and molecular weight (MW) of the guest polymers. In addition, a strategy is proposed to identify the drug candidates with the potential to form ICs with polymers, which may help to expand the range of drug-polymer co-crystals.

Formulation aspects of Solid Dispersions of Simvastatin

The aim of the present work was to improve dissolution rate of Simvastatin, a drug used for the treatment of hyperlipidemia. Simvastatin is a selective competitive inhibitor of HMG CoA reductase. However its absolute bioavailability is 5 % hence to increase it further solid dispersions were prepared. Solid dispersions were prepared with PVP-K30 at different drug: polymer ratios. These solid dispersions were analyzed for in-vitro dissolution profile, and solid dispersions of drug with PVP-K30 at all drug: polymer ratios had shown improved dissolution rate. FTIR studies showed no interactions among drug and polymers. The study shows that the dissolution rate of Simvastatin can be enhanced to considerable extent by solid dispersion technique with PVP-K30. From the above study it can be concluded that solid dispersion of Simvastatin improved the drug dissolution profile. It was found that by varying the drug polymer ratio and by using different methods of preparation of solid dispersion, the dissolution rate of pure drug can be enhanced. The present work concluded that solid dispersion technology can be used successfully to enhance the dissolution rate of poorly soluble drugs.

Pharmaceutical evaluation of atorvastatin calcium tablets available on the Internet: A preliminary investigation of substandard medicines in Japan

Substandard medicine is a type of substandard/spurious/falsely labeled/falsified/counterfeit (SSFFC) drug as defined by the WHO that has permeated the distribution of drugs on the Internet, and is accessible without prescription. An influx of substandard medicines is thus a serious matter in many developed countries. Here, Lipitor and its generic drugs containing atorvastatin calcium (ATC), used for the treatment of hyperlipidemia worldwide, were selected as a model prescription drug. Six brands of ATC tablets were purchased from four Japanese-language web sites. Raman spectroscopy and powder X-ray diffraction (PXRD) were employed to determine ATC and ingredients in the tablets. Although PXRD measurements showed no diffraction peaks of ATC because of its low content, a handheld Raman spectrometer detected ATC in unmodified tablets (without crushing). The tablets were assayed for drug content and dissolution profile according to the Japanese Pharmacopoeia, and one product showed an obviously slower drug release. X-ray computed tomography (CT) showed the interior of the tablet in detail and suggested that massive agglomerations caused slow disintegration of the tablet. This is the first report applying X-ray CT to tablets obtained on the Internet and indicates that unqualified prescription drugs are easily distributed on the Internet without any quality assurance.

Hybrid aerogel preparations as drug delivery matrices for low water-solubility drugs

A comprehensive study of 14 hybrid aerogels of different composition with applications in drug delivery has been carried out. The overall objective was to modulate the release behavior of drug-impregnated aerogels, from an almost instantaneous release to a semi-retarded delivery prolonged during several hours, through internal surface functionalization. The designed hybrid aerogels were composed of silica and gelatin and functionalized with either phenyl, long (16) hydrocarbon chain or methyl moiety. As model systems, three class II active agents (pKa<5.5), ibuprofen, ketoprofen and triflusal, were chosen to impregnate the aerogels. The work relied on the use of supercritical fluid technology for both the synthesis and functionalization of the hybrid aerogels, as well as for the impregnation with an active agent using supercritical CO2 as a solvent. For the impregnated aerogels, in vitro release profiles were recorded under gastric and intestinal pH-conditions using HPLC techniques. The release behavior observed for the three studied drugs was explained considering the measured dissolution profiles of the crystalline drugs, the aerogel composition and its functionalization. Such features are considered of great interest to tailor the bioavailability of drugs with low water solubility.

In vitro dissolution methodology, mini-Gastrointestinal Simulator (mGIS), predicts better in vivo dissolution of a weak base drug, dasatinib

USP apparatus I and II are gold standard methodologies for determining the in vitro dissolution profiles of test drugs. However, it is difficult to use in vitro dissolution results to predict in vivo dissolution, particularly the pH-dependent solubility of weak acid and base drugs, because the USP apparatus contains one vessel with a fixed pH for the test drug, limiting insight into in vivo drug dissolution of weak acid and weak base drugs. This discrepancy underscores the need to develop new in vitro dissolution methodology that better predicts in vivo response to assure the therapeutic efficacy and safety of oral drug products. Thus, the development of the in vivo predictive dissolution (IPD) methodology is necessitated. The major goals of in vitro dissolution are to ensure the performance of oral drug products and the support of drug formulation design, including bioequivalence (BE).Orally administered anticancer drugs, such as dasatinib and erlotinib (tyrosine kinase inhibitors), are used to treat various types of cancer. These drugs are weak bases that exhibit pH-dependent and high solubility in the acidic stomach and low solubility in the small intestine (>pH 6.0). Therefore, these drugs supersaturate and/or precipitate when they move from the stomach to the small intestine. Also of importance, gastric acidity for cancer patients may be altered with aging (reduction of gastric fluid secretion) and/or co-administration of acid-reducing agents. These may result in changes to the dissolution profiles of weak base and the reduction of drug absorption and efficacy. In vitro dissolution methodologies that assess the impact of these physiological changes in the GI condition are expected to better predict in vivo dissolution of oral medications for patients and, hence, better assess efficacy, toxicity and safety concerns. The objective of this present study is to determine the initial conditions for a mini-Gastrointestinal Simulator (mGIS) to assess in vivo dissolution of BCS class IIb drugs, dasatinib as a model drug, including the different gastric condition.The maximum dissolution of dasatinib with USP dissolution apparatus II was less than 1% in pH 6.5 SIF, while the one with mGIS (pH 1.2 SGF/pH 6.5 SIF) reached almost 100%. The supersaturation and precipitation of dasatinib were observed in the in vitro dissolution studies with mGIS but not with USP apparatus II. Additionally, dasatinib dissolution with mGIS was reduced to less than 10% when the gastric pH was elevated, suggesting the co-administration of acid reducing agents will decrease the oral bioavailability of dasatinib.Accurate prediction of in vivo drug dissolution would be beneficial for assuring product safety and efficacy for patients. To this end, we have created a new in vitro dissolution system, mGIS, to predict the in vivo dissolution phenomena of a weak base drug, dasatinib. The experimental results when combined with in silico simulation suggest that the mGIS predicted the in vivo dissolution well due to the elevation of gastric pH. Thus, mGIS might be suitable to predict in vivo dissolution of weak basic drugs. This mGIS methodology is expected to significantly advance the prediction of in vivo drug dissolution. It is also expected to assist in optimizing product development and drug formulation design in support of Quality by Design (QbD) initiatives.