Influence of selected water soluble carbohydrates on the dissolution profile of prednisolone

Abstract

The utilization of three water soluble carbohydrates as carrier to improve the dissolution rate of prednisolone was studied. Coprecipitates and physical mixtures of the drug and the carriers in three different proportions were prepared and their dissolution profile was compared with the dissolution profile of the pure drug. The remarkably fast and erratic dissolution of prenisolone observed from the coprecipitates was possible due to the conversion of prednisolone into its metastable or amorphous form durning the coprecipitation process. The dissolution rate of the drug from the physical mixtures was much higher than from the pure drug itself. Effect of aging of the coprecipitate on the dissolution profile showed an increasing tendency of the dissolution curve to match with that of the corresponding physical mixture.     

The development of a modified dissolution method suitable for investigating powder mixtures

A novel dissolution method was developed, suitable for powder mixtures, based on the USP basket apparatus. The baskets were modified such that the powder mixtures were retained within the baskets and not dispersed, a potential difficulty that may arise when using conventional USP basket and paddle apparatus. The advantages of this method were that the components of the mixtures were maintained in close proximity, maximizing any drug: excipient interaction and leading to more linear dissolution profiles. Two weakly acidic model drugs, ibuprofen and acetaminophen, and a selection of pharmaceutical excipients, including potential dissolution-enhancing alkalizing agents, were chosen for investigation. Dissolution profiles were obtained for simple physical mixtures. The f1 fit factor values, calculated using pure drug as the reference material, demonstrated a trend in line with expectations, with several dissolution enhancers apparent for both drugs. Also, the dissolution rates were linear over substantial parts of the profiles. For both drugs, a rank order comparison between the f1 fit factor and calculated dissolution rate, obtained from the linear section of the dissolution profile, demonstrated a correlation using a significance level of P = 0.05. The method was proven to be suitable for discriminating between the effects of excipients on the dissolution of the model drugs. The method design produced dissolution profiles where the dissolution rate was linear for a substantial time, allowing determination of the dissolution rate without mathematical transformation of the data. This method may be suitable as a preliminary excipient-screening tool in the drug formulation development process.     

Nimesulide-modified gum karaya solid mixtures: preparation, characterization, and formulation development

Solid mixtures of nimesulide (NS) and modified gum karaya (MGK) were prepared to improve the dissolution rate of NS. The effect of drug-carrier ratio on dissolution rate of NS was investigated by preparing the solid mixtures of different ratios by cogrinding method. Solid mixtures were also prepared by physical mixing, kneading, and solid dispersion techniques to study the influence of method of preparation. Differential Scanning Calorimetry (DSC), X-ray Diffraction (XRD), and equilibrium solubility studies were performed to explain the results of in vitro dissolution rate studies. It was clearly evident from the results that the NS dissolution rate was dependent on the concentration of MGK in the solid mixtures, and optimum weight ratio was found to be 1:4 (NS:MGK). Though the dissolution rate of NS from all solid mixtures prepared by different methods improved significantly, maximum improvement in dissolution rate was observed with solid dispersions. The order of methods basing on their effect on dissolution efficiency is solid dispersion > kneading > cogrinding > physical mixing > pure NS. Tablets of pure drug and solid mixtures (1:4 w/w, NS:MGK) were prepared. Though the best results from the dissolution test were obtained for the tablets containing solid dispersions, tablets containing cogrinding mixture were found to be suitable, from a practical point of view, for commercialization.     

Drug dispersion degree and drug dissolution rate in Hybrane S1200-based instant-release matricial particles prepared by hot melt extrusion

The objective of this study is to evaluate the dissolution of a poorly soluble drug (prednisolone) from different sized matricial particles (from <250 to >1500?µm) with two drug contents (10% or 20%) obtained by hot melt extrusion using the hyperbranched polyesteramide Hybrane S1200 (water-soluble and with a Tg of 45?°C) as the carrier. X-ray diffraction, differential scanning calorimetry and SEM studies permit us to conclude that in 10% prednisolone extrudate, the drug is mainly dispersed within the carrier, whereas in those containing 20% an important fraction of the drug remains in a crystalline state and is accumulated on the surface of the extrudates. On particles proceeding from 10% drug extrudate, the drug dissolution rate is very high and slightly dependant on particle size and in all cases, higher than the pure micronized drug. However, on particles proceeding from 20% prednisolone extrudate particle size have a major effect on drug dissolution rate, attributable to higher proportions of crystalline drug accumulated on the surface, hindering polymer dissolution. Thus, the reduction of the particle size after extrudate grinding creates new surfaces from inside, that leads to strong increments on prednisolone dissolution rate, and becomes higher than the pure micronized drug one when the particle size is <250?µm.     

Dissolution Rate Study of Fresh and Aging Triamterene-Urea Solid Dispersions

Triamterene-urea solid dispersions of varying weight fractions were elaborated by the melting carrier method and their dissolution profiles compared with the pure drug and physical mixtures. The dissolution rates of triamterene from solid dispersions were faster than the pure drug and physical mixtures.

Solubility studies revealed a linear increase in the solubility of the triamterene with the increase of urea concentration.

The intrinsic dissolution rates, determined by the rotating disc method, showed linear dissolution profiles in spite of that the scanning electron microscopy examination revealed that the surfaces do not maintain constant during the dissolution process.

Aging of the different preparations for one year at room temperature does not induced significant changes in their dissolution profiles.     

Dissolution Rate Study of Fresh and Aging Triamterene-Urea Solid Dispersions

Triamterene-urea solid dispersions of varying weight fractions were elaborated by the melting carrier method and their dissolution profiles compared with the pure drug and physical mixtures. The dissolution rates of triamterene from solid dispersions were faster than the pure drug and physical mixtures.

Solubility studies revealed a linear increase in the solubility of the triamterene with the increase of urea concentration.

The intrinsic dissolution rates, determined by the rotating disc method, showed linear dissolution profiles in spite of that the scanning electron microscopy examination revealed that the surfaces do not maintain constant during the dissolution process.

Aging of the different preparations for one year at room temperature does not induced significant changes in their dissolution profiles.     

Enhanced solubility of piperine using hydrophilic carrier-based potent solid dispersion systems

Context: Piperine alkaloid, an important constituent of black pepper, exhibits numerous therapeutic properties, whereas its usage as a drug is limited due to its poor solubility in aqueous medium, which leads to poor bioavailability.

Objective: Herein, a new method has been developed to improve the solubility of this drug based on the development of solid dispersions with improved dissolution rate using hydrophilic carriers such as sorbitol (Sor), polyethylene glycol (PEG) and polyvinyl pyrrolidone K30 (PVP) by solvent method. Physical mixtures of piperine and carriers were also prepared for comparison.

Methods: The physicochemical properties of the prepared solid dispersions were examined using SEM, TEM, DSC, XRD and FT-IR. In vitro dissolution profile of the solid dispersions was recorded and compared with that of the pure piperine and physical mixtures. The effect of these carriers on the aqueous solubility of piperine has been investigated.

Results: The solid dispersions of piperine with Sor, PEG and PVP exhibited superior performance for the dissolution of piperine with a drug release of 70%, 76% and 89%, respectively after 2?h compared to physical mixtures and pure piperine, which could be due to its transformation from crystalline to amorphous form as well as the attachment of hydrophilic carriers to the surface of poorly water-soluble piperine.

Conclusion: Results suggest that the piperine solid dispersions prepared with improved in vitro release exhibit potential advantage in delivering poorly water-soluble piperine as an oral supplement.     

Evaluation of solid dispersions of Clofazimine

Clofazimine (CLF) was formulated with polyethylene glycol (PEG) and polyvinyl pyrrolidone (PVP) as a solid solid dispersion (SSD) to increase the aqueous solubility and dissolution rate of the drug. Different molecular weights of PEG (1500, 4000, 6000, and 9000 Da) and PVP (14,000 and 44,000 Da) were used in different drug:carrier weight ratios (1:1, 1:5, and 1:9) and their effect on the dissolution performance of the drug was evaluated in USP Type 2 apparatus using 0.1 N HCl medium. The dissolution rate was compared with corresponding physical mixtures, a currently marketed soft gelatin capsule product, and free CLF. The effect of different methods of preparation (solvent/melt) on the dissolution rate of CLF was evaluated for PEG solid dispersions. Saturation solubility and phase solubility studies were carried out to indicate drug:carrier interactions in liquid state. Infrared (IR) spectroscopy and X-ray diffraction (XRD) were used to indicate drug:carrier interactions in solid state. Improvement in the drug dissolution rate was observed in solid dispersion formulations as compared to the physical mixtures. The dissolution rate improved with the decreasing weight fraction of the drug in the formulation. Polyvinyl pyrrolidone solid dispersion systems gave a better drug release profile as compared to the corresponding PEG solid dispersions. The effect of molecular weight of the PEG polymers did not follow a definite trend, while PVP 14,000 gave a better dissolution profile as compared to PVP 44,000. Improvement in saturation solubility of the drug in the solid dispersion systems was noted in all cases. Further, IR spectroscopy indicated drug:carrier interactions in solid state in one case and XRD indicated reduction in the crystallinity of CLF in another. It was concluded that solid-dispersion formulations of Clofazimine can be used to design a solid dosage form of the drug, which would have significant advantages over the currently marketed soft gelatin capsule dosage form.     

Evaluation of Solid Dispersions of Clofazimine

ABSTRACT

Clofazimine (CLF) was formulated with polyethylene glycol (PEG) and polyvinyl pyrrolidone (PVP) as a solid solid dispersion (SSD) to increase the aqueous solubility and dissolution rate of the drug. Different molecular weights of PEG (1500, 4000, 6000, and 9000 Da) and PVP (14,000 and 44,000 Da) were used in different drug:carrier weight ratios (1:1, 1:5, and 1:9) and their effect on the dissolution performance of the drug was evaluated in USP Type 2 apparatus using 0.1 N HCl medium. The dissolution rate was compared with corresponding physical mixtures, a currently marketed soft gelatin capsule product, and free CLF. The effect of different methods of preparation (solvent/melt) on the dissolution rate of CLF was evaluated for PEG solid dispersions. Saturation solubility and phase solubility studies were carried out to indicate drug:carrier interactions in liquid state. Infrared (IR) spectroscopy and X-ray diffraction (XRD) were used to indicate drug:carrier interactions in solid state. Improvement in the drug dissolution rate was observed in solid dispersion formulations as compared to the physical mixtures. The dissolution rate improved with the decreasing weight fraction of the drug in the formulation. Polyvinyl pyrrolidone solid dispersion systems gave a better drug release profile as compared to the corresponding PEG solid dispersions. The effect of molecular weight of the PEG polymers did not follow a definite trend, while PVP 14,000 gave a better dissolution profile as compared to PVP 44,000. Improvement in saturation solubility of the drug in the solid dispersion systems was noted in all cases. Further, IR spectroscopy indicated drug:carrier interactions in solid state in one case and XRD indicated reduction in the crystallinity of CLF in another. It was concluded that solid-dispersion formulations of Clofazimine can be used to design a solid dosage form of the drug, which would have significant advantages over the currently marketed soft gelatin capsule dosage form.     

Dissolution performance related to particle size distribution for cohpiercially available prednisolone acetate suspensions

Dissolution performance for three commercially available parenteral prednisolone acetate suspensions was analyzed using a diffusion based model. Physicochemical properties of the drug and particle size characteristics of the formulation were included in the model as important determinants of dissolution performance.

The model describes the dissolution profile for each formulation with a single characteristic value, the dissolution rate constant. For Products I and II with similar particle size characteristics, the model sufficiently describes the dissolution profile for each formulation but does not provide conclusive evidence about reasons for differences in dissolution performance between the two products. For Product III, the model sufficiently describes the dissolution profile and adequately includes the effect of a bimodal distribution of larger drug particles .

This approach to the analysis of dissolution data for suspension formulations is suggested as being useful during the formulation process to provide for predetermined dissolution characteristics, as an evaluative tool in quality assurance, assurance, and for correlating in-vivo and in-vitro product performance.     

Preparation and characterization of spironolactone-loaded gelucire microparticles using spray-drying technique

The basic objectives of this study were to prepare and characterize solid dispersions of poorly soluble drug spironolactone (SP) using gelucire carriers by spray-drying technique. The properties of the microparticles produced were studied by differential scanning calorimetry (DSC), scanning electron microscopy, saturation solubility, encapsulation efficiency, and dissolution studies. The absence of SP peaks in DSC profiles of microparticles suggests the transformation of crystalline SP into an amorphous form. The in vitro dissolution test showed a significant increase in the dissolution rate of microparticles as compared with pure SP and physical mixtures (PMs) of drug with gelucire carriers. Therefore, the dissolution rate of poorly water-soluble drug SP can be significantly enhanced by the preparation of solid dispersion using spray-drying technique.     

Dissolution performance related to particle size distribution for cohpiercially available prednisolone acetate suspensions

Abstract

Dissolution performance for three commercially available parenteral prednisolone acetate suspensions was analyzed using a diffusion based model. Physicochemical properties of the drug and particle size characteristics of the formulation were included in the model as important determinants of dissolution performance.

The model describes the dissolution profile for each formulation with a single characteristic value, the dissolution rate constant. For Products I and II with similar particle size characteristics, the model sufficiently describes the dissolution profile for each formulation but does not provide conclusive evidence about reasons for differences in dissolution performance between the two products. For Product III, the model sufficiently describes the dissolution profile and adequately includes the effect of a bimodal distribution of larger drug particles.

This approach to the analysis of dissolution data for suspension formulations is suggested as being useful during the formulation process to provide for predetermined dissolution characteristics, as an evaluative tool in quality assurance, assurance, and for correlating in-vivo and in-vitro product performance.     

Influence of Montmorillonite on the Dissolution and Bioavailablity of Phenyton

The dissolution of phenytoin were studied from various phentyoin-montmorillonite combinations. Firstly, phentoin-montmorllionite combinations were obtained by precipitating phenytoin from two different solvents on to montmorillonite using drug to montmorillonite ratios. Secondly, physical mixtures of phenytoin and montmorillonite were prepared in were compressed into tablets and the dissolution rates were determined. The dissolution rates of phenytoin with the dissolution rates of the combinations. The montmorillonite increased the dissolution rate of phenyton from all the combinations to such an extent that the dissolution rates compressed well with those obtained form phenytoin sodium.

The bioavailability of phentyoin from three different phenytoin-montmorillonite mixutres were compared well the bioavailability from a phenytoin sodium capsule in four volunters. More phenytoin were absorbed from the phenytoin-montrillonite mixtures than from the phenytoin sodium. The absorption rate of phenytoin from the three different montmorillonite mixtures were fastef than from the phenytoin sodium capsule for the first hour, after administtration. After one hour the phenytoin blood levels from the phenytoin-montmorillonite mixtures started to level of to reach lower peak concentrations in plasma than that obtained from phenytoin-montmorillonite mixtures (1:1 and 1:9 ratios) was more than that absorbed form phenytoin sodium. The advantages of combining phenytoin and montmorillonite for the improvement of the bioavailability of phenytoin have clearly been demonstrated.     

Improved Dissolution of Indomethacin in Coprecipitates with Phospholipids-I

Indomethacin powders were blended with phospholipids to prepare physical mixtures or made into solid dispersions by the solvent method and their comparative dissolution profiles were studied. Indomethacin exhibited significantly improved dissolution rates in phospholipid coprecipitates compared to either the physical mixtures or the pure indomethacin. The coprecipitates of lecithin-indomethacin 1:16 weight ratio had a 6.5 fold greater initial dissolution rate, and the total amount dissolved after 60 minutes was 140% greater compared to indomethacin alone. Increasing the lecithin content to 1:4 resulted in only a modest additional increase in the initial dissolution rate (40%) and the limiting concentration (14%)     

Preparation and in Vitro Dissolution Profiles of Tolazamide-Polyethylene Glycol Solid Dispersions

The objective of this study is to prepare solid dispersions of tolazamide (TLZ) using polyethylene glycol (PEG) and measure the dissolution of TLZ. PEG 8000 was used as carrier to prepare solid dispersions by melt and solvent methods. Dissolution studies indicated a remarkable increase in the rate of dissolution of TLZ when dispersed in PEG as well as with physical mixture of TLZ and PEG. The rate of dissolution of TLZ was faster with solid dispersions containing TLZ:PEG (1:5) and (1:10) compared to physical mixtures and pure TLZ. The effect of buffer on dissolution was studied. In general the dissolution of TLZ was less in phosphate buffered saline (PBS, pH 7.4) compared to Tris buffer. However, there was no significant difference in the extent of dissolution of TLZ from solid dispersions and physical mixture compared to pure TLZ. Solid dispersions prepared by solvent method showed faster dissolution rates compared to melt method. These results suggest that the rate of dissolution can be increased by improving the wetting property of tolazamide.     

Preparation of a Solid Dispersion by a Dropping Methodto Improve the Rate of Dissolution of Meloxicam

Application of a solid dispersion system is one of the methods used to increase the bioavailability of poorly water-soluble drugs. Adaptation of the dropping method from the chemical industry as a formulation procedure may help the scaling-up process and simplify the formulation of poorly water-soluble compounds. Meloxicam (ME), a nonsteroidal anti-inflammatory drug that is poorly soluble in water, and polyethylene glycol (PEG) 4000, a water-soluble carrier, were formulated by using a dropping method in an attempt to improve the dissolution of ME. Pure ME and physical mixtures and tablets of ME–PEG 4000 (1:3 ratio) were compared as regards their dissolution with samples formulated by the dropping method. The results revealed that the round particles (solid drops) exhibited a higher dissolution rate than those of the physical mixtures, tablets, and pure ME. Self-modeling curve resolution (SMCR) as a chemometric method was used to evaluate X-ray powder diffractometry (XRPD) data. The results demonstrated the presence of a new crystalline phase in the solid dispersion, which can help the fast and quantitative dissolution from the solid drops. The round particles can be adapted to individual therapy by using a distributor.     

Preparation of a solid dispersion by a dropping method to improve the rate of dissolution of meloxicam

Application of a solid dispersion system is one of the methods used to increase the bioavailability of poorly water-soluble drugs. Adaptation of the dropping method from the chemical industry as a formulation procedure may help the scaling-up process and simplify the formulation of poorly water-soluble compounds. Meloxicam (ME), a nonsteroidal anti-inflammatory drug that is poorly soluble in water, and polyethylene glycol (PEG) 4000, a water-soluble carrier, were formulated by using a dropping method in an attempt to improve the dissolution of ME. Pure ME and physical mixtures and tablets of ME-PEG 4000 (1:3 ratio) were compared as regards their dissolution with samples formulated by the dropping method. The results revealed that the round particles (solid drops) exhibited a higher dissolution rate than those of the physical mixtures, tablets, and pure ME. Self-modeling curve resolution (SMCR) as a chemometric method was used to evaluate X-ray powder diffractometry (XRPD) data. The results demonstrated the presence of a new crystalline phase in the solid dispersion, which can help the fast and quantitative dissolution from the solid drops. The round particles can be adapted to individual therapy by using a distributor.     

Solubility and Dissolution of Etoposide from Solid Dispersions of PEG 8000

The Solubility and dissolution of etoposide from solid dispersion of PEG 8000, prepared by the fusion method, were investigated. Stability studies revealed that the etoposide was stable in water for three days at 37 ± 0.5°C alone and as a physical mixture with PEG 8000. However, nearly 5% decomposition was oberved in aqueous solutions made from solid dispersions. TLC, IR and HPLC studies showed both the drug and carrier were stable during the fusion process. Aqueous solubility of etoposide from solid dispersions with etoposide: PEG 8000 ratios of 1:5, 1:10, 1:20, 1:30 and 1:40, was studied at 37 ± 0.5°C, and found to be significantly higher than that of etoposide alone or from its physical mixtures with PEG 8000. These dispersions increased the solubility of etoposide by 32.3%, 96.8%, 133.5%, 280.7% and 326.6% respectively compared to that of etoposide alone, whereas only 1:40 etoposide: PEG 8000 physical mixture demonstrated a significant increase in etoposide solubility (16.1%). Dissolution studies, on the solid dispersions in water at 37 ± 0.5°C, revealed a marked increase in the dissolution rate of etoposide from 1:20, 1:30 and 1:40 solid dispersions with 100% drug dissolving within 1 minute; dissolution time for 1:5 and 1:10 dispersions, and all physical mixtures was 3 minutes while etoposide alone required 30 minutes for complete drug dissolution. The melting behavior of the etoposide-PEG 8000 mixtures and subsequent thermal analysis of the melts suggested that the increase of solubility of etoposide was mostly due to the formation of a solid solution of etoposide in PEG 8000.     

Solid State Interaction of Raloxifene HCl with Different Hydrophilic Carriers During Co-grinding and its Effect on Dissolution Rate

This study investigated the effects of different classes of hydrophilic carriers (poly vinyl pyrrolidones [PVPs] [Plasdone K-25 and Plasdone S-630], cellulosic polymers [hydroxypropyl methyl cellulose and hydroxy propyl cellulose], and Sodium Alginate) on the solid state and dissolution rate of Raloxifene hydrochloride (R-HCl). Solid state characterizations of co-ground mixtures and physical mixtures in 1:1 and 1:2 ratios of drug to polymer were performed by employing laser diffractometer for particle size and differential scanning calorimetry (DSC) for solid state interactions. The results of particle size studies showed that only co-grinding with PVPs was more effective in the reduction of particle size than the milling of drug alone. DSC study indicated that the crystalline nature of the drug was reduced after co-grinding with PVPs when compared with their corresponding physical mixtures. The hydrophilic carriers other than PVPs did not reduce the crystalline nature of the drug significantly. X-ray diffraction and scanning electron microscopy were carried out for selected batches to confirm DSC results. Significant enhancement in dissolution rate and extent was observed with co-ground mixtures of drug and PVPs. Plasdone S-630 was found to be a better carrier for R-HCl in terms of achieving improvement in dissolution. In vitro dissolution data can be described by Hixson–Crowell model, indicating the drug release mechanism predominated by erosion.     

Characterization and Dissolution Study of Oxodipine from Solid Binary Systems

Thennomicroscopy and differential scanning calorimetry were employed to characterize solid binary systems prepared with oxodipine and PEG 6000, 2-hydroxypropyl-β-cyclodextrin or mannitol. DSC curves did not allow to diferentiate physical mixtures from solid dispersions. Thennomicroscopy revealed the interactions that can be produced between drug and each carrier, due to heat contribution, when the physical mixtures were observed; also this thermal technique permited us to ascertain the composition of particles that constitute the solid dispersions. Dissolution studies showed that the amelioration obtained in oxodipine dissolution from physical mixtures was due to the dessagregant action of the carriers, which obtained an increase of the drug surface in contact with the dissolution medium. The proportions and carrier nature influence the oxodipine dissolution, fundamentally from solid dispersions, where the interaction drug/carrier is stronger than in physical mixtures.