Preparation and Characterization of Solid Dispersions of Piroxicam with Hydrophilic Carriers

ABSTRACT

The objective of this study was to improve the dissolution rate of a poor water soluble drug, piroxicam, by solid dispersion technique. Solid dispersions were prepared by three different methods depending on the type of carrier. The dissolution rate of piroxicam was markedly increased in solid dispersion of myrj 52, Eudragit® E100 and mannitol. Solubility studies revealed a marked increase in the solubility of piroxicam with an increase in myrj 52 and Eudragit® E100 concentrations. Data from the X-ray diffraction and FT-IR spectroscopy showed that piroxicam was amorphous in the solid dispersions prepared with dextrin and Eudragit® E100.     

The incorporation of low-substituted hydroxypropyl cellulose into solid dispersion systems

While the use of amorphous solid dispersions to improve aqueous solubility is well documented, little consideration has traditionally been given to the finished dosage form. The objective of this study was to evaluate the dissolution performance of amorphous solid dispersions containing a dispersed superdisintegrant with binding properties. KinetiSol® dispersing was used to thermally process hypromellose acetate succinate-based compositions containing the drug substance nifedipine (NIF) and a highly compressible grade of low-substituted hydroxypropyl cellulose (New Binder Disintegrants; NBD-grade). Solid-state analysis demonstrated that compositions were rendered amorphous during processing. Tablets containing intra-dispersion NBD were found to exhibit non-sink dissolution performance similar to milled intermediate, demonstrating excellent disintegration characteristics. Conversely, tablets without intra-dispersion NBD were found to release significantly less NIF during dissolution analysis due to particle agglomeration. It was determined that compressibility and particle wetting increased as the level of intra-dispersion NBD increased.     

Production of advanced solid dispersions for enhanced bioavailability of itraconazole using KinetiSol® Dispersing

Objectives: To investigate the ability of KinetiSol® Dispersing to prepare amorphous solid dispersions of itraconazole using concentration-enhancing polymers. Methods: Concentration-enhancing nature of several cellulosic polymers (HPMC, hypromellose acetate succinate) was studied using a modified in vitro dissolution test. Solid dispersions were prepared by KinetiSol® Dispersing and characterized for solid-state properties using X-ray diffraction and differential scanning calorimetry. Potency and release characteristics were also assessed by high-performance liquid chromatography. Oral bioavailability of lead formulations was also assessed in animal models. Results: Screening studies demonstrated superior concentration-enhancing performance from the hypromellose acetate succinate polymer class. Data showed that stabilization was related to molecular weight and the degree of hydrophobic substitution on the polymer such that HF > MF ≈ LF, indicating that stabilization was achieved through a combination of steric hindrance and hydrophobic interaction, supplemented by the amphiphilic nature and ionization state of the polymer. Solid dispersions exhibited amorphous solid-state behavior and provided neutral media supersaturation using a surfactant-free pH change method. Rank-order behavior was such that LF > MF > HF. Addition of Carbopol 974P increased acidic media dissolution, while providing a lower magnitude of supersaturation in neutral media because of swelling of the high viscosity gel. In vivo results for both lead compositions displayed erratic absorption was attributed to the variability of gastrointestinal pH in the animals. Conclusions: These results showed that production of amorphous solid dispersions containing concentration-enhancing polymers through KinetiSol® Dispersing can provide improved oral bioavailability; however, additional formulation techniques must be developed to minimize variability associated with natural variations in subject gastrointestinal physiology.     

Solubility and dissolution performances of spray-dried solid dispersion of Efavirenz in Soluplus

Abstract

Efavirenz (EFV), a first-line anti-HIV drug largely used as part of antiretroviral therapies, is practically insoluble in water and belongs to BCS class II (low solubility/high permeability). The aim of this study was to improve the solubility and dissolution performances of EFV by formulating an amorphous solid dispersion of the drug in polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer (Soluplus^®) using spray-drying technique. To this purpose, spray-dried dispersions of EFV in Soluplus^® at different mass ratios (1:1.25, 1:7, 1:10) were prepared and characterized using particle size measurements, SEM, XRD, DSC, FTIR and Raman microscopy mapping. Solubility and dissolution were determined in different media. Stability was studied at accelerated conditions (40?°C/75% RH) and ambient conditions for 12 months. DSC and XRD analyses confirmed the EFV amorphous state. FTIR spectroscopy analyses revealed possible drug–polymer molecular interaction. Solubility and dissolution rate of EFV was enhanced remarkably in the developed spray-dried solid dispersions, as a function of the polymer concentration. Spray-drying was concluded to be a proper technique to formulate a physically stable dispersion of amorphous EFV in Soluplus^®, when protected from moisture.     

Investigating the effect of moisture protection on solid-state stability and dissolution of fenofibrate and ketoconazole solid dispersions using PXRD,HSDSC and Raman microscopy

Enhanced dissolution of poorly soluble active pharmaceutical ingredients (APIs) in amorphous solid dispersions often diminishes during storage due to moisture-induced re-crystallization. This study aims to investigate the influence of moisture protection on solid-state stability and dissolution profiles of melt-extruded fenofibrate (FF) and ketoconazole (KC) solid dispersions. Samples were kept in open, closed and Activ-vials^® to control the moisture uptake under accelerated conditions. During 13-week storage, changes in API crystallinity were quantified using powder X-ray diffraction (PXRD) (Rietveld analysis) and high sensitivity differential scanning calorimetry (HSDSC) and compared with any change in dissolution profiles. Trace crystallinity was observed by Raman microscopy, which otherwise was undetected by PXRD and HSDSC. Results showed that while moisture protection was ineffective in preventing the re-crystallization of amorphous FF, KC remained X-ray amorphous despite 5% moisture uptake. Regardless of the degree of crystallinity increase in FF, the enhanced dissolution properties were similarly diminished. Moisture uptake above 10% in KC samples also led to re-crystallization and significant decrease in dissolution rates. In conclusion, eliminating moisture sorption may not be sufficient in ensuring the stability of solid dispersions. Analytical quantification of API crystallinity is crucial in detecting subtle increase in crystallinity that can diminish the enhanced dissolution properties of solid dispersions.     

Dissolution,Solubility, XRD,and DSC Studies on Flurbiprofen-Nicotinamide Solid Dispersions

Flurbiprofen-nicotinamide solid dispersions were prepared by the fusion method. The solid dispersions were evaluated for dissolution rate. The drug-carrier interaction in the liquid and solid states were studied by using phase solubility analysis, phase diagram, X-ray diffraction (XRD), and differential scanning calorimentry (DSC). Solid dispersions gave fast and rapid dissolution of flurbiprofen compared with the pure drug and the physical mixture. Phase diagram and DSC indicated that flurbiprofen and nicotinamide form a eutectic mixture. The aqueous solubility of flurbiprofen was enhanced in the presence of nicotinamide.     

Dissolution, solubility, XRD, and DSC studies on flurbiprofen-nicotinamide solid dispersions

Flurbiprofen-nicotinamide solid dispersions were prepared by the fusion method. The solid dispersions were evaluated for dissolution rate. The drug-carrier interaction in the liquid and solid states were studied by using phase solubility analysis, phase diagram, X-ray diffraction (XRD), and differential scanning calorimentry (DSC). Solid dispersions gave fast and rapid dissolution of flurbiprofen compared with the pure drug and the physical mixture. Phase diagram and DSC indicated that flurbiprofen and nicotinamide form a eutectic mixture. The aqueous solubility of flurbiprofen was enhanced in the presence of nicotinamide.     

Dissolution, Solubility, XRD, and DSC Studies on Flurbiprofen-Nicotinamide Solid Dispersions

Flurbiprofen-nicotinamide solid dispersions were prepared by the fusion method. The solid dispersions were evaluated for dissolution rate. The drug-carrier interaction in the liquid and solid states were studied by using phase solubility analysis, phase diagram, X-ray diffraction (XRD), and differential scanning calorimentry (DSC). Solid dispersions gave fast and rapid dissolution of flurbiprofen compared with the pure drug and the physical mixture. Phase diagram and DSC indicated that flurbiprofen and nicotinamide form a eutectic mixture. The aqueous solubility of flurbiprofen was enhanced in the presence of nicotinamide.     

Dissolution, Bioavailability and Ulcerogenic Studies on Solid Dispersions of Indomethacin in Water Soluble Cellulose Polymers

The dissolution rate, bioavailability and ulcerogenic activity of indomethacin dispersed in water soluble cellulose polymers was investigated. Solid dispersions of indomethacin in hydroxypropyl cellulose-SL (HPC-SL), hydroxypropylmethyl cellulose (HPMC) and hydroxyethyl cellulose (HEC) were prepared by common solvent method with a view to improve its dissolution and absorption characteristics. The dispersions were evaluated by X-ray diffraction, TLC, IR, dissolution rate, bioavailability and ulcerogenic studies. TLC and IR studies indicated no interaction between indomethacin and carriers. Indomethacin in the dispersions was found to be in amorphous form. Marked increase in the dissolution rate and efficiency of indomethacin was observed in the case of solid dispersions. HPC-SL gave the highest dissolution improvement. A 30-fold increase in dissolution was observed with indomethacin-HPC-SL (9:1) dispersion.

In vivo studies in human subjects showed a significant increase in absorption rate (k_a) and serum levels of indomethacin with solid dispersions when compared to indomethacin alone. However, the extent of bioavailabilty was the same with both indomethacin and its solid dispersions. About 70-80 per cent reduction in ulcerogenic activity was observed with solid dispersions and the dispersions were found to have negligible ulcerogenic activity.     

Lonidamine Solid Dispersions: In Vitro and In Vivo Evaluation

ABSTRACT

Solid dispersions of lonidamine in PEG 4000 and PVP K 29/32 were prepared by the spray-drying method. Then, the binary systems were studied and characterized using differential scanning calorimetry, hot stage microscopy, and x-ray diffractometry. In vitro dissolution studies of the solid dispersed powders were performed to verify if any lonidamine dissolution rate or water solubility improvement occurred. In vivo tests were carried out on the solid dispersions and on the cyclodextrin inclusion complexes to verify if this lonidamine water solubility increase was really able to improve the in vivo drug plasma levels. Drug water solubility was increased by the solid dispersion formation, and the extent of increase depended on the polymer content of the powder. The greater increase of solubility corresponded to the highest content of polymer. Both the solid dispersions and the cyclodextrin complexes were able to improve the in vivo bioavailability of the lonidamine when administered per os. Particularly, the AUC of the drug plasma levels was increased from 1.5 to 1.9-fold depending on the type of carrier.     

Effect of semicrystalline polymers on self-emulsifying solid dispersions of nateglinide: in vitro and in vivo evaluation

This study was undertaken to improve solubility and bioavailability of nateglinide by preparation of stable self-emulsifying solid dispersions (SESDs). The influence of semicrystalline polymers (poloxamer 407, gelucire 50/13) and method of preparation on dissolution behavior, in vivo performance and stability of nateglinide SESDs were investigated. After optimization, SESDs were prepared at 1:5 weight ratio of nateglinide and polymer individually. All the SESDs were characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, X-ray diffraction and scanning electron microscopy. Aqueous solubility of nateglinide was enhanced by 91.82-fold. The SESDs (poloxamer 407-based solid dispersions) achieved rapid and complete drug release (～100% within 45?min) at pH 2. The improved dissolution appeared to be well correlated with the enhanced bioavailability of nateglinide in rabbits. After oral administration of SESDs (poloxamer 407-based solid dispersions), C_max and AUC of nateglinide were increased by ～2.92 and 1.77-folds, respectively, signifying the effectiveness of solid dispersions to improve the bioavailability of nateglinide. Stability during storage was established to show prevention of recrystallization. In conclusion, SESDs with poloxamer 407 in solvent method appeared to be an economic and promising technique to improve the dissolution, bioavailability, and stability of nateglinide.     

Preparation and characterization of solid dispersions of piroxicam with hydrophilic carriers

The objective of this study was to improve the dissolution rate of a poor water soluble drug, piroxicam, by solid dispersion technique. Solid dispersions were prepared by three different methods depending on the type of carrier. The dissolution rate of piroxicam was markedly increased in solid dispersion of myrj 52, Eudragit^® E100 and mannitol. Solubility studies revealed a marked increase in the solubility of piroxicam with an increase in myrj 52 and Eudragit^® E100 concentrations. Data from the X-ray diffraction and FT-IR spectroscopy showed that piroxicam was amorphous in the solid dispersions prepared with dextrin and Eudragit^® E100.     

Lonidamine solid dispersions: in vitro and in vivo evaluation

Solid dispersions of lonidamine in PEG 4000 and PVP K 29/32 were prepared by the spray-drying method. Then, the binary systems were studied and characterized using differential scanning calorimetry, hot stage microscopy, and x-ray diffractometry. In vitro dissolution studies of the solid dispersed powders were performed to verify if any lonidamine dissolution rate or water solubility improvement occurred. In vivo tests were carried out on the solid dispersions and on the cyclodextrin inclusion complexes to verify if this lonidamine water solubility increase was really able to improve the in vivo drug plasma levels. Drug water solubility was increased by the solid dispersion formation, and the extent of increase depended on the polymer content of the powder. The greater increase of solubility corresponded to the highest content of polymer. Both the solid dispersions and the cyclodextrin complexes were able to improve the in vivo bioavailability of the lonidamine when administered per os. Particularly, the AUC of the drug plasma levels was increased from 1.5 to 1.9-fold depending on the type of carrier.     

Use of highly compressible Ceolus™ microcrystalline cellulose for improved dosage form properties containing a hydrophilic solid dispersion

The development of amorphous solid dispersions containing poorly soluble drug substances has been well-documented; however, little attention has been given to the development of the finished dosage form. The objective of this study was to investigate the use of Ceolus(?) microcrystalline cellulose, a highly compressible excipient, for the production of rapidly disintegrating tablets containing a hydrophilic solid dispersion of a poorly soluble drug, indomethacin. Solid dispersions of indomethacin and Kollidon(?) VA64 were prepared by hot melt extrusion and characterized for amorphous nature. Milled dispersion particles at 500 mg/g drug loading were shown to be amorphous by differential scanning calorimetry and provided rapid dissolution in sink conditions. Physical characterization of the milled extrudate showed that the particle size of the intermediate was comparable with Ceolus(?) PH-102 and larger than the high compressibility grades of microcrystalline cellulose selected for the trial (Ceolus(?) KG-802, Ceolus(?) UF-711). Preliminary tableting trials showed that dissolution performance was significantly reduced for formulations at dispersion loadings in excess of 50%. Using a mixture design of experiments (DOE), the levels of PH-102, KG-802, UF-711, and PH-301 were optimized. Trials revealed a synergistic relationship between conventional grades (PH-102 and PH-301) and highly compressible grades (KG-802 and UF-711) leading to improved compression characteristics and more rapid dissolution rates. The formulation and resulting compressibility were also shown to have an impact on in vitro supersaturation indicating tablet formulation could impact oral bioavailability. Through the use of highly compressible microcrystalline cellulose grades such as Ceolus(?) KG-802 and UF-711, it may be possible to maximize the bioavailability benefit of amorphous solid dispersions administered as tablet dosage forms.     

Classification of solid dispersions: correlation to (i) stability and solubility (ii) preparation and characterization techniques

Solid dispersion has been a topic of interest in recent years for its potential in improving oral bioavailability, especially for poorly water soluble drugs where dissolution could be the rate-limiting step of oral absorption. Understanding the physical state of the drug and polymers in solid dispersions is essential as it influences both the stability and solubility of these systems. This review emphasizes on the classification of solid dispersions based on the physical states of drug and polymer. Based on this classification, stability aspects such as crystallization tendency, glass transition temperature (T_g), drug polymer miscibility, molecular mobility, etc. and solubility aspects have been discussed. In addition, preparation and characterization methods for binary solid dispersions based on the classification have also been discussed.     

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.     

Properties of Solid Dispersions of Naproxen in Various Polyethylene Glycols

Abstract

Solid dispersions of naproxen in polyethylene glycol 4000, 6000, and 20000, aimed at improving the drug dissolution characteristics, were prepared by both the solvent and melting methods. The drug-polymer interaction in the solid state was investigated using differential scanning calorimetry, hot-stage microscopy, Fourier-transform infrared spectroscopy, and x-ray diffraction analysis. Interaction in solution was studied by phase solubility analysis and dissolution experiments. Computer-aided molecular modeling was used to supplement the results from phase solubility studies. No important chemical interaction was found between naproxen and polyethylene glycol, either in solution or in the solid state, apart from the formation of weak drug-polymer hydrogen bonds. The increase of naproxen dissolution rate from its binary systems with polyethylene glycol could be attributed to several factors such as improved wettability, local solubilization, and drug particle size reduction. No influence of polymer molecular weight or of the solid dispersion preparation method on drug dissolution properties was found.     

Dissolution rate enhancement,in vitro evaluation and investigation of drug release kinetics of chloramphenicol and sulphamethoxazole solid dispersions

Formulation of solid dispersions is one of the effective methods to increase the rate of solubilization and dissolution of poorly soluble drugs. Solid dispersions of chloramphenicol (CP) and sulphamethoxazole (SX) as model drugs were prepared by melt fusion method using polyethylene glycol 8000 (PEG 8000) as an inert carrier. The dissolution rate of CP and SX were rapid from solid dispersions with low drug and high polymer content. Characterization was performed using fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). FTIR analysis for the solid dispersions of CP and SX showed that there was no interaction between PEG 8000 and the drugs. Hyper-DSC studies revealed that CP and SX were converted into an amorphous form when formulated as solid dispersion in PEG 8000. Mathematical analysis of the release kinetics demonstrated that drug release from the various formulations followed different mechanisms. Permeability studies demonstrated that both CP and SX when formulated as solid dispersions showed enhanced permeability across Caco-2 cells and CP can be classified as well-absorbed compound when formulated as solid dispersions.     

Part II: Bioavailability in Beagle Dogs of Nimodipine Solid Dispersions Prepared by Hot-Melt Extrusion

ABSTRACT

The aim of the present work was to investigate the in vitro dissolution properties and oral bioavailability of three solid dispersions of nimodipine. The solid dispersions were compared with pure nimodipine, their physical mixtures, and the marketed drug product Nimotop®. Nimodipine solid dispersions were prepared by a hot-melt extrusion process with hydroxypropyl methylcellulose (HPMC, Methocel E5), polyvinylpyrrolidone/vinyl acetate copolymer (PVP/VA, Plasdone S630®), and ethyl acrylate, methyl methacrylate polymer (Eudragit® EPO). Previous studies of XRPD and DSC data showed that the crystallinity was not observed in hot-melt extrudates, two T_gs were observed in the 30% and 50% NMD-HPMC samples, indicating phase separation. The weakening and shift of the N–H stretching vibration of the secondary amine groups of nimodipine as determined by FT-IR proved hydrogen bonding between the drug and polymers in the solid dispersion. The dissolution profiles of the three dispersion systems showed that the release was improved compared with the unmanipulated drug. Drug plasma concentrations were determined by HPLC, and pharmacokinetic parameters were calculated after orally administering each preparation containing 60 mg of nimodipine. The mean bioavailability of nimodipine was comparable after administration of the Eudragit® EPO solid dispersion and Nimotop®, but the HPMC and PVP/VA dispersions exhibited much lower bioavailability. However, the AUC_{0–12 hr} values of all three solid dispersions were significantly higher than physical mixtures with the same carriers and nimodipine powder.     

Biopharmaceutical Studies on Solid Dispersions of Nalidixic Acid in Modified Starches

Abstract

The objective of the study is to improve the dissolution rate and efficiency and bioavailability of nalidixic acid (NA) and to evaluate three modified starches namely dextrin (D) β-cyclodextrin (β-CD) and hydroxyethyl starch (HES) as carriers for solid dispersions. Solid dispersions of NA in D, β-CD and HES were prepared by common solvent method and the dispersions were evaluated by TLC, IR, DTA, X-ray diffraction, moisture absorption, dissolution rate and bioavailability studies. The three modified starches were found to be non-hygroscopic, non-interacting carriers giving solid dispersions and effective in increasing the dissolution rate, efficiency and absorption rate of NA. A marked reduction in the crystallinity and crystal size of NA in the dispersions was observed.