Investigation of dissolution enhancement of itraconazole by solid dispersion in superdisintegrants

Solid dispersions of itraconazole (ITR) in lactose, microcrystalline cellulose (MCC), and three superdisintegrants (Primogel, Kollidon CL, and Ac-Di-Sol) and their formulation into tablets were investigated with an objective of enhancing the dissolution rate of ITR from tablet formulations. X-ray diffraction (XRD) and differential scanning calorimetry (DSC) were used to characterize the dispersions. A marked enhancement in the dissolution rate of ITR was observed with all the excipients. The order for the excipients to enhance the dissolution rate was Ac-Di-Sol > Kollidon CL > Primogel > MCC > lactose. Solid dispersions in superdisintegrants gave much higher rates of dissolution than the dispersions in other excipients. Ac-Di-Sol gave the most improvement (28-fold) in the dissolution rate of ITR at a 1:1 drug:excipient ratio. Solid dispersions in superdisintegrants could be formulated into tablets. These tablets, apart from fulfilling all official and other specifications, exhibited higher rates of dissolution and dissolution efficiency (DE) values. XRD indicated the presence of ITR in amorphous form in the dispersions. DSC indicated a weak interaction between ITR and the excipients. Micronization and conversion of the drug into the amorphous form and the fast disintegrating and dispersing action of the superdisintegrants contribute to the enhancement of the dissolution rate of ITR from its solid dispersions in superdisintegrants and their corresponding tablet formulations.     

Investigation of Dissolution Enhancement of Itraconazole by Solid Dispersion in Superdisintegrants

Solid dispersions of itraconazole (ITR) in lactose, microcrystalline cellulose (MCC), and three superdisintegrants (Primogel, Kollidon CL, and Ac-Di-Sol) and their formulation into tablets were investigated with an objective of enhancing the dissolution rate of ITR from tablet formulations. X-ray diffraction (XRD) and differential scanning calorimetry (DSC) were used to characterize the dispersions. A marked enhancement in the dissolution rate of ITR was observed with all the excipients. The order for the excipients to enhance the dissolution rate was Ac-Di-Sol > Kollidon CL > Primogel > MCC > lactose. Solid dispersions in superdisintegrants gave much higher rates of dissolution than the dispersions in other excipients. Ac-Di-Sol gave the most improvement (28-fold) in the dissolution rate of ITR at a 1:1 drug: excipient ratio. Solid dispersions in superdisintegrants could be formulated into tablets. These tablets, apart from fulfilling all official and other specifications, exhibited higher rates of dissolution and dissolution efficiency (DE) values. XRD indicated the presence of ITR in amorphous form in the dispersions. DSC indicated a weak interaction between ITR and the excipients. Micronization and conversion of the drug into the amorphous form and the fast disintegrating and dispersing action of the superdisintegrants contribute to the enhancement of the dissolution rate of ITR from its solid dispersions in superdisintegrants and their corresponding tablet formulations.     

In vitro and in vivo characterization of fast dissolving tablets containing gliquidone–pluronic solid dispersion

Abstract

The main objective of this study is to increase the dissolution rate of gliquidone using its solid dispersions with pluronic F-68 by solvent evaporation method. The solid dispersion of the drug with pluronic at ratio 1:3 showed the highest dissolution efficiency (50.7%) after 10?min, so it was incorporated in fast dissolving tablets. Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) were used to study the interaction between gliquidone and pluronic in the solid state. The FTIR spectroscopic studies revealed no chemical interaction between the drug and pluronic, while the DSC results indicated the amorphous state of gliquidone in the solid dispersion. A 3² full factorial design was used to study the effect of varying concentrations of croscarmellose and sodium starch glycolate as superdisintegrants on the disintegration time and the percentage released after 10?min. The optimized formula showed a disintegration time of 39.1?±?1.2?s and 85.43%?±?5.16% released after 10?min and was selected for the in-vivo studies in rabbits. The selected formula showed significant enhancement of gliquidone bioavailability, about 1.8 times compared with the commercial Glurenor tablets.     

Co-crystallization for enhanced dissolution rate of bicalutamide: preparation and evaluation of rapidly disintegrating tablets

Objectives: Enhance the dissolution rate of bicalutamide via co-crystallization with sucralose (sweetener), with the aim to develop rapidly disintegrating tablets with subsequent prompt dissolution.

Significance: Bicalutamide is antiandrogenic agent for the treatment of prostate cancer but has low and variable oral bioavailability, mainly attributed to poor dissolution. Co-crystallization with benign excipients is promising for dissolution enhancement with the additive serving dual functions. The benefit will become greater if dissolution enhancement is associated with the development of orodispersible tablets which is suitable for elderly patients who are the most vulnerable for prostate cancer.

Methods: Bicalutamide was dissolved in acetone in the presence of increasing molar ratios of sucralose. The solvent was evaporated while mixing to deposit crystals that were subjected to wet co-grinding until drying. The developed solids were characterized using Fourier transform infrared spectroscopy, differential thermal analysis and X-ray diffraction in addition to monitoring bicalutamide dissolution.

Results: Instrumental analysis provided evidences for co-crystallization which was initiated at 1:1 molar ratio of bicalutamide to sucralose with complete co-crystallization at 1:4 molar ratio. The co-crystals provided faster bicalutamide dissolution compared with the unprocessed drug and that recrystalized from acetone in the absence of sucralose. The formulation containing bicalutamide with sucralose at 1:4 molar ratio was selected for tablet formulation into which superdisintegrants were included. The developed tablets exhibited flash disintegration with subsequent fast dissolution of bicalutamide.

Conclusions: The study introduced co-crystallization of bicalutamide with sucralose as an efficient tool to enhance the dissolution rate and to develop rapidly dissolving tablets for intraoral administration.     

Formulation and evaluation of rapidly disintegrating fenoverine tablets: effect of superdisintegrants

The objective of this study was to formulate directly compressible rapidly disintegrating tablets of fenoverine with sufficient mechanical integrity, content uniformity, and acceptable palatability to assist patients of any age group for easy administration. Effect of varying concentrations of different superdisintegrants such as crospovidone, croscarmellose sodium, and sodium starch glycolate on disintegration time was studied. Tablets were evaluated for weight variation, thickness, hardness, friability, taste, drug content, in vitro and in vivo disintegration time, and in vitro drug release. Other parameters such as wetting time, water absorption ratio ('R'), and drug-excipient compatibility were also evaluated. The disintegration time of the best rapidly disintegrating tablet formulation among those tested was observed to be 15.9 sec in vitro and 37.16 sec in vivo. Good correlation was observed between disintegration time and 'R' for each of the three superdisintegrants at the concentrations studied. Considering the 'R' values and disintegration time, crospovidone was significantly superior (p < 0.05) compared to the other superdisintegrants tested. Release of drug was faster from formulations containing 6% crospovidone (CP 6) compared to the marketed fenoverine (Spasmopriv(R)) capsules. Similarity factor 'f(2)' (51.5) between dissolution profiles of the rapidly disintegrating tablet formulation CP 6 and the marketed formulation indicated that the two dissolution profiles were similar. Differential scanning calorimetric studies did not indicate any excipient incompatibility, either during mixing or after compression. In conclusion, directly compressible rapidly disintegrating tablets of fenoverine with lower friability, acceptable taste, and shorter disintegration times were obtained using crospovidone and other excipients at optimum concentrations.     

Influence of admixed citric acid and physiological variables on the vinpocetine release from sodium alginate compressed matrix tablets

In this study, the controlled release matrix tablets of vinpocetine were prepared by direct compression using sodium alginate (SAL) as hydrophilic polymer and different amounts of citric acid as hydrosoluble acidic excipient to set up a system bringing about zero-order release of this drug in distilled water containing 0.5% sodium dodecyl sulfate. At the critical content of admixed citric acid (60 mg/tab.), the lowest drug-release rate was observed. In order to explain the effect of this critical content on drug-release rate from SAL matrices, investigation of the possibility of interaction of citric acid with SAL was performed using differential scanning calorimetric analysis and infrared analysis, which confirmed the existence of direct citric acid-SAL interaction when these two excipients came in contact with water. A zero-order drug-release system could be obtained by regulating the ratio of citric acid-to-SAL and the capacity of this system in controlling drug-release rate depended on the extent of interaction between citric acid and SAL. It is worth noticing that pH and the ionic strength of the dissolution medium were found to exert an influence on the drug-release performance of SAL tablets.     

Optimization of Digoxin Tablets

Abstract

Four digoxin tablets have been formulated using potassium chloride and urea as water soluble directly compressible fillers. Simple blending and solvent deposition techniques were used for drug incorporation. The physical characteristics and content uniformity of the formulated tablets were comparable to those of two commercial brands of digoxin tablets. However, the dissolution rate of digoxin from tablets prepared by solvent deposition either on potassium chloride or urea (% dissolution after 1 h was 94 and 83 respectively) was higher than that from tablets made by simple blending (39 and 45% respectively)and superior to that of the two commercial brands (75.5% for both).     

Enhancement of dissolution rate and anti-inflammatory effects of piroxicam using solvent deposition technique

Piroxicam solid depositions were prepared by means of the solvent deposition technique using different concentrations of microcrystalline cellulose as carrier material. The solvent deposition system (SDS) with drug to carrier ratio of 1:9 had a rapid dissolution rate in vitro. When this SDS was administered perorally to rats with a previous experimentally induced inflammation in their paws, it exhibited a pronounced anti-inflammatory action. X-ray diffraction and infrared (IR) spectroscopy showed no differences in the crystal state of piroxicam in SDS formulation and physical mixture of piroxicam and carrier. The increase in the dissolution rate and consequent enhancement of anti-inflammatory effect of piroxicam in SDS were attributed to the reduced particle size of drug deposited on the carrier and enhanced wettability of the particles brought about by the carrier.     

Formulation and Evaluation of Rapidly Disintegrating Fenoverine Tablets: Effect of Superdisintegrants

The objective of this study was to formulate directly compressible rapidly disintegrating tablets of fenoverine with sufficient mechanical integrity, content uniformity, and acceptable palatability to assist patients of any age group for easy administration. Effect of varying concentrations of different superdisintegrants such as crospovidone, croscarmellose sodium, and sodium starch glycolate on disintegration time was studied. Tablets were evaluated for weight variation, thickness, hardness, friability, taste, drug content, in vitro and in vivo disintegration time, and in vitro drug release. Other parameters such as wetting time, water absorption ratio (‘R’), and drug-excipient compatibility were also evaluated. The disintegration time of the best rapidly disintegrating tablet formulation among those tested was observed to be 15.9 sec in vitro and 37.16 sec in vivo. Good correlation was observed between disintegration time and ‘R’ for each of the three superdisintegrants at the concentrations studied. Considering the ‘R’ values and disintegration time, crospovidone was significantly superior (p < 0.05) compared to the other superdisintegrants tested. Release of drug was faster from formulations containing 6% crospovidone (CP 6) compared to the marketed fenoverine (Spasmopriv®) capsules. Similarity factor ‘f₂’ (51.5) between dissolution profiles of the rapidly disintegrating tablet formulation CP 6 and the marketed formulation indicated that the two dissolution profiles were similar. Differential scanning calorimetric studies did not indicate any excipient incompatibility, either during mixing or after compression. In conclusion, directly compressible rapidly disintegrating tablets of fenoverine with lower friability, acceptable taste, and shorter disintegration times were obtained using crospovidone and other excipients at optimum concentrations.     

Improving Dissolution Rates of Griseofulivin by Deposition on Disintegrants

The dissolution rate of griseofulvin was markedly enhanced by the solvent deposited on the disintegrants of Primojel, Mobile Starch and Nymcel.

The enahancement of the dissolution rate of the solvent deposition systems was due eto the effects of wetting and deaggreation of the disintegrants. The dissolution of the grisefulvin from the Primojel system was at a higher rate than the other systems. This was attributed to the smaller particle size of the griseofulvin in the Primojel system. The tablets of the Primojel system demonstrated the highest dissolution rate. This was resulted form the fast disintegration time of the tablets and the small particle size of the griseofulvin.     

Formation of Amorphous Telmisartan Polymeric Microparticles for Improvement of Physicochemical Characteristics

In order to improve solubility and dissolution rate of poorly aqueous soluble telmisartan, its amorphous polymeric microparticles with PVP K30 were prepared with or without aid of adsorbent (Aerosil200/Sylysia350) using spray-drying technique. The pure drug and formulations were evaluated for their morphology, particle size, aqueous solubility, and in vitro drug release. Solid state characterization of pure drug and microparticles was carried out by Fourier transform infrared spectroscopy (FTIR), x-ray powder diffraction (XRPD), scanning electron microscopy (SEM), and differential scanning calorimetry (DSC). FTIR indicated hydrogen bonding interaction with an absence of any other chemical interaction between drug and excipient. The results of DSC and XRPD revealed transformation of crystalline drug to amorphous form which was confirmed by SEM. Significant solubility and dissolution enhancement was observed for all polymeric microparticles over pure drug and spray-dried pure drug. This enhancement was attributed to the wetting effect of polymers, altered surface morphology with micronization and decreased crystallinity of drug particles.     

The Effect of Excipient Solubility on the in-vitro and in-vivo Properties of Bendrofluazide Tablets 5 MG

SUMMARY

TaRblets containing bendrofluazide 5 mg have been prepared at 190, 220 and 290 MNm^-2 using four different excipients; sorbitol, lactose, calcium orthophosphate and calcium hydrogen orthophosphate. The solubilities in water of the excipients were respectively 70, 17.8, 0.03 and 0.01% W/W. Granules prepared under identical conditions were found to have moisture contents of about 3% W/W. All the four excipients were found to be equally effective in producing minimal tablet to tablet weight variation. Tablet hardness was governed by the intrinsic nature of the excipient and for all diluents an increase in compressional force produced an increase in tablet hardness. However, the size of this hardness increase varied markedly dependent on the excipient. Disintegration time and the nature of the disintegrating process varied greatly with the excipient. Generally, decreasing the solubility of the diluent decreased the disintegration time, but the pattern was complicated by the effect of compaction pressure which produced marked disintegration time differences with some excipients but not with others. No correlation was found between disintegration time and dissolution rate. However changing the excipient greatly affected the dissolution rates of the tablets in some cases by as much as 600%. Disintegration time was found to be no indicator of dissolution performance. In-vivo assessment of the tablets demonstrated that there was a direct correlation between in-vivo activity, measured as initial micturation rate, with bendro-fluazide dissolution. In general the study showed that by changing the diluent, marked differences in the in-vivo and in-vitro properties of the bendrofluazide tablets could be demonstrated and that these differences were more marked using very soluble excipients. The best excipients were found to be calcium orthophosphate and calcium hydrogen orthophosphate. Sorbitol was found to be the least useful as a tablet diluent.     

Effect of water-soluble carriers on dissolution characteristics of nifedipine solid dispersions

Solid dispersions of nifedipine (NP) with polyethylene glycols (PEG4000 and PEG6000), hydroxypropyl-β-cyclodextrin (HPβCD), and poloxamer 407 (PXM 407) in four mixing ratios were prepared by melting, solvent, and kneading methods in order to improve the dissolution of NP. The enhancement of the dissolution rate and the time for 80% NP dissolution T_80% depended on the mixing ratio and the preparation method. The highest dissolution rate and the T_80% as short as 15 min were obtained from PXM 407 solid dispersion prepared by the melting method at the mixing ratio of 1:10. The X-ray diffraction (XRD) patterns of solid dispersions at higher proportions of carriers demonstrated consistent with the results from differential scanning calorimetric (DSC) thermograms that NP existed in the amorphous state. The wettability and solubility were markedly improved in the PXM 407 system. The presence of intermolecular hydrogen bonding between NP and PEGs and between HPβCD and PXM 407 was shown by infrared (IR) spectroscopy.     

Co-processed κ-carrageenan-pectin as pelletizing aid for immediate-release pellets

This study investigates the extrusion-spheronization performance of some mixtures of co-processed κ-carrageenan and pectin (as excipient), and sodium starch glycolate (as superdisintegrant). Attention is focused with an objective to improve the mechanical stability and the dissolution rate of poorly soluble domperidone (as a model drug). Initially, co-processed κ-carrageenan-pectin excipient is prepared with different ratios of κ-carrageenan and pectin. Different marketed brands of κ-carrageenan (Gelcarin, Aquagel and Eugel) were employed and dried by solvent evaporation method. Further characterization was carried out by SEM, XRD and FTIR analysis. Pellets were prepared using extrusion-spheronization technique. Pellets were evaluated for flow properties, particle size, sphericity, tensile strength, friability, disintegration time and in-vitro drug release studies. Solid-state characterization of pellets was also done by FTIR, DSC and SEM analysis. The mechanical stability and dissolution rate of prepared pellets were found to be dependent on the concentration of pectin and type of κ-carrageenan employed in the fabrication of pellets. The pellets made with a high proportion of Eugel showed a very high dissolution rate of domperidone and undergo rapid disintegration validating co-processed k-carrageenan-pectin as a promising pelletizing aid for immediate-release pharmaceutical formulations.     

New co-processed MCC-based excipient for fast release of low solubility drugs from pellets prepared by extrusion-spheronization

In this study, a new co-processed excipient composed of microcrystalline cellulose (MCC), sorbitol, chitosan and Eudragit® E, easily obtained by wet massing, to increase the dissolution rate of active ingredients of low water solubility from pellets prepared by extrusion–spheronization is evaluated. Indomethacin, nifedipine, furosemide, ibuprofen, prednisolone and hydrochlorothiazide are used as model drugs of different solubility. All pellet formulations evaluated showed adequate morphological, flow and mechanical properties. Pellets prepared with the co-processed excipient show a higher drug dissolution rate than those prepared with MCC and even higher than the pure drug powder. The fast drug dissolution and the complete disintegration (<3?min) of the pellets can be explained by the great porosity of the formulations, the high solubility of the sorbitol, the disintegrant capacity of the chitosan and the distribution of the Eudragit® E polymer particles in-between the other components of the co-processed mixture. In conclusion, this new co-processed excipient is very suitable to increase the dissolution rate of poorly soluble drugs from pellets prepared by extrusion–spheronization. Moreover, the drug release rate can be estimated from the Ln of the drug solubility in acidic medium.     

Formulation and pharmacokinetics of gelucire solid dispersions of flurbiprofen

Context: Development of solid dispersions is to improve the therapeutic efficacy by increasing the drug solubility, dissolution rate, bioavailability as well as to attain rapid onset of action.

Objective: The present research deals with the development of solid dispersions of flurbiprofen which is poorly water soluble to improve the solubility and dissolution rate using gelucires.

Materials and methods: In this study, solid dispersions were prepared following solvent evaporation method using gelucire 44/14 and gelucire 50/13 as carriers in different ratios. Then the formulations were evaluated for different physical parameters, solubility studies, DSC, FTIR studies and in vitro dissolution studies to select the best formulation that shows rapid dissolution rate and finally subjected to pharmacokinetic studies.

Results and discussion: From the in vitro dissolution study, formulation F3 showed the better improvement in solubility and dissolution rate. From the pharmacokinetic evaluation, the control tablets produced peak plasma concentration (C_max) of 9140.84?±?614.36?ng/ml at 3?h T_max and solid dispersion tablets showed C_max?=?11?445.46?±?149.23?ng/ml at 2?h T_max. The area under the curve for the control and solid dispersion tablets was 31?495.16?±?619.92 and 43?126.52?±?688.89?ng h/ml and the mean resident time was 3.99 and 3.68?h, respectively.

Conclusion: From the above results, it is concluded that the formulation of gelucire 44/14 solid dispersions is able to improve the solubility, dissolution rate as well as the absorption rate of flurbiprofen than pure form of drug.     

Multivariate Analysis of Variance of Dissolution Data in the Development of Oral Sustained Release Formulations

A multivariate analysis of variance applied to polinomial interpretation of growth curves in used for the interpretation of dissolution curves of four experimental, sustained release, wax type theophylline tablets.

The factors under study were glyceril palmitic stearate, carboxypol imethylene contents and compression force. The tablets were formulated according an experimental design based on 4 × 4 Hadamard matrix. The USP type I apparatus for dissolution test and CHI 0.1 N plus O.1%. polysorbate 80 as dissolution medium was used.

The statistical interpretation of results showed: first, that dissolution rates were almost constant for the four formulations during 8 h; second, the main difference between formulation dissolution rates can be inputed to fat excipient content and in much lesser extent to carboxipolymethylene content; third, the theopylline release rate was unaffected by compression force.     

Controlled-Release Theophylline Tablet Formulations Containing Acrylic Resins,III. Influence of Filler Excipient.

Abstract

The selection of a filler excipient was demonstrated to have a dramatic effect on the release properties of theophylline from matrix tablets containg an acrylic resin polymer as the retardant substance. Theophylline tablets were formulated to contain 60 percent drug, 28 percent filler excipient, 10 percent Eudragit S100, 1.5 percent fumed silica and 0.5 percent magnesium stearate. Release rates were most rapid when microcrystalline cellulose was the filler excipient and the slowest when calcium sulfate was used as the diluent. Dissolution rates decreased in acidic medium as the level of Eudragit S100 increased from zero to fifteen percent. In pH 7.4 phosphate buffer, USP, the converse held true because of the high solubility of the resin at this pH value. There was no difference between dissolution rates at pH 1.1 and pH 4.0. Tablet porosity was influenced significantly by the filler excipient. Higher porosity usually resulted in greater theophylline dissolution rates. When sucrose was employed as the filler excipient, tablet porosity was inversely related to tablet hardness.     

Controlled-Release Theophylline Tablet Formulations Containing Acrylic Resins, III. Influence of Filler Excipient.

The selection of a filler excipient was demonstrated to have a dramatic effect on the release properties of theophylline from matrix tablets containg an acrylic resin polymer as the retardant substance. Theophylline tablets were formulated to contain 60 percent drug, 28 percent filler excipient, 10 percent Eudragit S100, 1.5 percent fumed silica and 0.5 percent magnesium stearate. Release rates were most rapid when microcrystalline cellulose was the filler excipient and the slowest when calcium sulfate was used as the diluent. Dissolution rates decreased in acidic medium as the level of Eudragit S100 increased from zero to fifteen percent. In pH 7.4 phosphate buffer, USP, the converse held true because of the high solubility of the resin at this pH value. There was no difference between dissolution rates at pH 1.1 and pH 4.0. Tablet porosity was influenced significantly by the filler excipient. Higher porosity usually resulted in greater theophylline dissolution rates. When sucrose was employed as the filler excipient, tablet porosity was inversely related to tablet hardness.     

Preparation of theophylline-hydroxypropylmethylcellulose matrices using supercritical antisolvent precipitation: a preliminary study

Several controlled release systems of drugs have been elaborated using a supercritical fluid process. Indeed, recent techniques using a supercritical fluid as a solvent or as an antisolvent are considered to be useful alternatives to produce fine powders. In this preliminary study, the effect of Supercritical Anti Solvent process (SAS) on the release of theophylline from matrices manufactured with hydroxypropylmethylcellulose (HPMC) was investigated. Two grades of HPMC (HPMC E5 and K100) as carriers were considered in order to prepare a sustained delivery system for theophylline which was used as a model drug. The characterization of the drug before and after SAS treatment, and the coprecipitates with carriers, was performed by X-ray Diffraction (XRD) and Differential Scanning Calorimetry (DSC). The dissolution rate of theophylline, theophylline-coprecipitates, and matricial tablets prepared with coprecipitates were determined. The physical characterizations revealed a substantial correspondence of the drug solid state before and after supercritical fluid treatment while drug-polymer interactions in the SAS-coprecipitates were attested. The dissolution studies of the matrices prepared compressing the coprecipitated systems showed that the matrices based on HPMC K100 were able to promote a sustained release of the drug. Further, this advantageous dissolution performance was found to be substantially independent of the pH of the medium. The comparison with the matrices prepared with untreated substances demonstrated that matrices obtained with SAS technique can provide a slower theophylline release rate. A new mathematical model describing the in vitro dissolution kinetics was proposed and successfully tested on these systems.