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.     

Influence of different polymers on crystallization tendency and dissolution behavior of cilnidipine in solid dispersions

Context: Cilnidipine (CN) is a novel dihydropyridine calcium antagonist that is practically insoluble in aqueous media and exhibits a low oral bioavailability or limited clinical efficacy.

Objective: This study investigated the effects of three commercial and chemically diverse polymers – PVP, PVP/VA and Soluplus – on crystallization tendency and in vitro dissolution profiles of CN in order to determine an optimum carrier for composing the preferred solid dispersion (SD) of CN.

Methods: All these co-evaporated systems were characterized up to 3 months by thermoanalytical (DSC), crystallographic (POM, PXRD), microscopic (SEM) and spectroscopic (FTIR) techniques.

Results: The results showed that the polymers could be sorted by their effects of inhibiting CN crystallization in the ascending order: Soluplus, PVP/VA, PVP. The sequence was in accordance with that of the strength of drug–polymer hydrogen bonds revealed by FTIR spectra. It could be ascribed to relative hydrogen-bonding acceptor strengths of N-vinylpyrrolidone moiety in the polymer molecules. On the other hand, all the SDs showed enhanced dissolution profiles compared to pure CN alone. On their effects of enhancing CN dissolution, the polymers could be sorted in the descending order: Soluplus, PVP, PVP/VA.

Conclusions: It implied that the dissolution behavior of CN could bear a close relationship to both hydration capacity and hydrogen-bonding interaction tendency of moieties of the polymers. It might suggest an optimal formulation for CN comprising both PVP and Soluplus.     

Effect of semicrystalline copolymers in solid dispersions of pioglitazone hydrochloride: in vitro-in vivo correlation

Objective: The study was aimed to improve the dissolution and bioavailability of developed stable amorphous solid dispersions (SDs) of pioglitazone hydrochloride (PGH), a poorly water-soluble drug.

Significance: Poor aqueous solubility of PGH was overcome by the design of SDs. Level A correlation demonstrated between in vitro release and bioavailability of PGH, suggest its biowaiver potential.

Methods: The effects of semicrystalline copolymers (poloxamer 407 and gelucire 50/13) and methods of preparations on dissolution behavior, in vivo performance, and stability of PGH SDs were investigated. All the SDs were characterized by FTIR, TGA, DSC, XRD, and SEM.

Results: FTIR and TGA showed the compatibility with the polymers. The significant change in melting pattern of the PGH observed in the DSC thermograms supported by XRD patterns & SEM indicated a change from a crystalline to an amorphous state. Gelucire 50/13 was observed to have greater ability to form SDs than poloxamer 407 in solvent evaporation method (SM). Prevention of recrystallization during storage suggested stability of the formulation. Gelucire 50/13 based SD, prepared by SM remarkably increased the dissolution within 15?min (87.27?±?2.25%) and was supported by dissolution parameters (Q₁₅, IDR, RDR, % DE, f₁, f₂). These SDs showed pH-dependent solubility. In vivo test showed significantly (p?<?.05) higher AUC_0–t and C_max, which were about 3.17 and 4.34 times that of the pure drug respectively.

Conclusion: Gelucire 50/13 was found to be a suitable carrier for SM for preparation of SDs of PGH as evident from increased dissolution and bioavailability.     

In vitro and in vivo effects of morin on the intestinal absorption and pharmacokinetics of olmesartan medoxomil solid dispersions

Abstract

Purpose: In-situ evaluation to corroborate morin effects on the intestinal absorption and pharmacokinetic behavior of freeze-dried OLM-loaded solid dispersions with Caco-2 and in-vivo studies

Methods: Intestinal transport and absorption studies were examined by Caco-2 permeability, in-situ single pass perfusion and closed-loop models along with in-vivo pharmacokinetic studies to evaluate and confirm the effect of P-gp-mediated activity of morin. We evaluated the intestinal membrane damage in the presence of morin by measuring the release of protein and lactate dehydrogenase (LDH) followed by using qualitative and quantitative morphometric analysis to describe the surface characteristics of intestinal epithelium.

Results: Morin showed the highest P_eff value 13.8?±?0.34?×?10^?6?cm/s in jejunum than ileum (p?<?.01) at 100?µM with absorption enhancement of 1.31-fold together with enhanced (p?<?.01) secretory transport of 6.27?±?0.27?×?10?^?6?cm/s in Caco-2 monolayer cells. Our findings noticed 2.37 (in-situ); 2.39 (in-vivo) and 1.43 (in-situ); 1.36 (in-vivo) fold increase in AUC_0–t with elevated C_max and shortened T_max for freeze-dried solid dispersion in the presence of morin as compared to pure OLM and freeze-dried solid dispersions without morin, respectively.

Conclusions: Our study demonstrated that increased solubilization through freeze-dried OLM-loaded solid dispersion together with efflux inhibition improved intestinal permeability to one system that might lead to novel solubilization and efflux pump inhibition as a novel alternative potential to increase oral absorption and bioavailability of OLM.     

Dissolution and bioavailability enhancement of alpha-asarone by solid dispersions via oral administration

Alpha (α)-asarone (1-propenyl-2,4,5-methoxybenzol) (ARE) has been extensively used to treat chronic obstructive pulmonary diseases (COPD), bronchial asthma, pneumonia, and epilepsy. Due to its poor solubility and bioavailability, ARE was clinically administered via intravenous injection. However, severe allergies were often reported due to the presence of solublizers in the injection formulation. In our study, we sought to explore the biopharmaceutical classification of ARE, elucidate the mechanisms behind ARE absorption, and to develop a viable formulation to improve the oral bioavailability of ARE. ARE was not a P-glycoprotein substrate, which was absorbed in the passive mode without site specificity in the gastrointestinal tract. Solid dispersions prepared using hydrophilic matrix materials such as Pluronic F68, and polyethylene glycol (PEG) of varying molecular weights (PEG4K, PEG10K, and PEG20K) were proven to significantly improve the dissolution of ARE in vitro and the oral bioavailability of ARE in rats, which represent a promising strategy for the oral administration of ARE and other BCS II compounds.     

Solid dispersions enhance solubility,dissolution, and permeability of thalidomide

Thalidomide (THD) is a BCS class II drug with renewed and growing therapeutic applicability. Along with the low aqueous solubility, additional poor biopharmaceutical properties of the drug, i.e. chemical instability, high crystallinity, and polymorphism, lead to a slow and variable oral absorption. In this view, we developed solid dispersions (SDs) containing THD dispersed in different self-emulsifying carriers aiming at an enhanced absorption profile for the drug. THD was dispersed in lauroyl macrogol-32 glycerides (Gelucire^® 44/14) and α-tocopherol polyethylene glycol succinate (Kolliphor^® TPGS), in the presence or absence of the precipitation inhibitor polyvinylpyrrolidone K30 (PVP K30), by means of the solvent method. Physicochemical analysis revealed the formation of semicrystalline SDs. X-ray diffraction and infrared spectroscopy analyses suggest that the remaining crystalline fraction of the drug in the SDs did not undergo polymorphic transition. The impact of the solubility-enhancing formulations on the THD biopharmaceutical properties was evaluated by several in vitro techniques. The developed SDs were able to increase the apparent solubility of the drug (up to 2–3x the equilibrium solubility) for a least 4?h. Dissolution experiments (paddle method, 75?rpm) in different pHs showed that around 80% of drug dissolved after 120?min (versus 40% of pure crystalline drug). Additionally, we demonstrated the enhanced solubility obtained via SDs could be translated into increased flux in a parallel artificial membrane permeability assay (PAMPA). In summary, the results demonstrate that SDs could be considered an interesting and unexplored strategy to improve the biopharmaceutical properties of THD, since SDs of this important drug have yet to be reported.     

Preparation,characterization and in vitro and in vivo evaluation of a solid dispersion of Naringin

Naringin (NA) is one of typical flavanone glycosides widely distributed in nature and possesses several biological activities including antioxidant, anti-inflammatory, and antiapoptotic. The aim of this study was to develop solid dispersion (SD) and to improve the dissolution rate and oral bioavailability of NA. NA–SD was prepared by the traditional preparation methods using PEG6000, F68, or PVP K30 as carrier at different drug to carrier ratios. According to the results of solubility and in vitro dissolution test, the NA–PEG6000 (1:3) SD was considered as an optimal formulation to characterize by Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry and powder X-ray diffraction. Furthermore, oral bioavailabilities of NA–PEG6000 (1:3) SD and NA–suspension with the same dosage were investigated in SD rats. The results confirmed the formation of SD and the pharmacokinetic parameters of NA–PEG6000 (1:3) SD (C_max?=?0.645?±?0.262?µg/ml, AUC_0–t?=?0.471?±?0.084?µg/ml?h) were higher than that of NA–suspension (C_max?=?0.328?±?0.183?µg/ml, AUC_0–t =?0.361?±?0.093?µg/ml?h). Based on the results, the SD is considered as a promising approach to enhance the dissolution rate and oral bioavailability of NA.     

Effects of solid dispersion and self-emulsifying formulations on the solubility,dissolution, permeability and pharmacokinetics of isorhamnetin,quercetin and kaempferol in total flavones of Hippophae rhamnoides L.

The aim of this study was to investigate the effects of solid dispersions (SD) and self-emulsifying (SE) formulations on the solubility and absorption properties of active components in total flavones of Hippophae rhamnoides L. (TFH). The solubility, dissolution rate, permeability and pharmacokinetics of isorhamnetin, quercetin and kaempferol in TFH SD/SE formulations and TFH were compared. The results showed that the solubility and dissolution rate of isorhamnetin, quercetin and kaempferol in SD/SE formulations were significantly enhanced compared to those in TFH, however, their intestinal permeability was comparable. The bioavailability of isorhamnetin, quercetin and kaempferol in rats remarkably increased after oral administration of TFH SD formulations compared to TFH, but there was no significant increase after oral administration of TFH SE formulations. The results of this study indicated the SD formulations on the improvement of pharmacokinetic properties of isorhamnetin, quercetin and kaempferol in TFH were much better than those of SE formulations. The improvement of pharmacokinetic properties of isorhamnetin, quercetin and kaempferol in TFH by SD formulations was probably ascribed to the enhancement of the solubility and dissolution of the three components, but was not relevant to the intestinal permeability. Therefore, as for herb extracts containing multiple components, especially for their major components with poor water solubility, solid dispersion formulations might have the better potential to enhance their bioavailability.     

Enhancement of solubility and bioavailability of ambrisentan by solid dispersion using Daucus carota as a drug carrier: formulation,characterization, in vitro,and in vivo study

Ambrisentan is an US FDA approved drug, it is the second oral endothelin A receptor antagonist known for the treatment of pulmonary arterial hypertension, but its oral administration is limited due to its poor water solubility. Hence, the objective of the investigation was focused on enhancement of solubility and bioavailability of ambrisentan by solid dispersion technique using natural Daucus carota extract as drug carrier. Drug carrier was evaluated for solubility, swelling index, viscosity, angle of repose, hydration capacity, and acute toxicity test (LD₅₀). Ambrisentan was studied for the saturation solubility, phase solubility, and Gibbs free energy change. Compatibility of drug and the natural carrier was confirmed by DSC, FTIR, and XRD. Solid dispersions were evaluated for drug content, solubility, morphology, in vitro, and in vivo study. Screening of the natural carrier showed the desirable properties like water solubility, less swelling index, less viscosity, and acute toxicity study revealed no any clinical symptoms of toxicity. Drug and carrier interaction study confirmed the compatibility to consider its use in the formulation. Formed particles were found to be spherical with smooth surface. In vitro studies revealed higher drug release from the solid dispersion than that of the physical mixture. Bioavailability study confirms the increased absorption and bioavailability by oral administration of solid dispersion. Hence, it can be concluded that the natural Daucus carota extract can be the better alternative source for the preparation of solid dispersion and/or other dosage forms for improving solubility and bioavailability.     

Characterization of solid dispersions of Patchouli alcohol with different polymers: effects on the inhibition of reprecipitation and the improvement of dissolution rate

Solid dispersion technique is known to be an effective approach for the polymer to keep drugs stable in the solid state, thereby improving the dissolution rate and oral bioavailability through inhibiting reprecipitation in supersaturated solution. In this study, to evaluate the inhibitory effect of polyethylene glycol-6000 (PEG), Polyvinylpyrrolidone K30 (PVP) and Aminoalkyl methacrylate copolymer (Eudragit), the reprecipitation profiles were observed from supersaturated solutions of Patchouli alcohol (PA) in the presence and absence of the polymers. Furthermore, the dissolution profiles of PA solid dispersions formulated with PEG, PVP or Eudragit were compared for investigating the effect on improving dissolution of each polymer. Solid dispersions formulated with Eudragit were found to result in solution with the highest extent of supersaturation. By contrast, PEG and PVP were less effective. At equivalent supersaturation, all three polymers are capable of mitigating reprecipitation relative to that of PA alone. In addition, in the PA solid dispersion with Eudragit (E-SD (1/3)), the highest concentration of supersaturation of PA was maintained for prolonged time. These results unambiguously indicate that it is imperative to select the appropriate polymer and drug/polymer ratio in addition to considering the stability of the supersaturated solution, which was generated following dissolution of amorphous solid dispersion.     

PVP and surfactant combined carrier as an effective absorption enhancer of poorly soluble astilbin in vitro and in vivo

Context: Astilbin is considered to be a new and promising immunosuppressant for immune related diseases, but limited in clinical application due to its poor water solubility, difficult oral absorption and low bioavailability.

Objective: The present work studied the effect of PVP and surfactant combined carrier on its capability to improve drug absorption.

Materials and methods: PVP K30-Tween 80 combined carries was applied into the astilbin solid dispersions, tested both in vivo in beagle dogs and in vitro in transport experiments across Caco-2 cell monolayers.

Results and discussion: In the animal studies a many fold increase in plasma AUC was observed for the solid dispersions of drug in PVP K30-Tween 80 combined carries compared to active pharmaceutical ingredient (API). The applicability of Caco-2 monolayers as a tool for predicting the in vivo transport behavior of Astilbin in combination with a solubility enhancing carries was shown. In vitro transport studies confirmed the effect of combined carries on the absorption behavior of the astilbin. MTT studies showed the cell viability gradually decreased with the increase of the drug concentration in a dose dependent manner for astilbin and that in solid dispersions. The permeability and apparent permeability coefficients (P_app) increased with drug in the Caco-2 cell.

Conclusion: In this study, it was found that PVP K30 and Tween 80 promoted the permeability of drugs best within a certain amount. For astilbin PVP K30 and surfactant combined carrier had a strong potential to improve oral bioavailability.     

绿原酸磷脂复合物固体分散体的体外溶出和药动学研究

为研究绿原酸磷脂复合物固体分散体(CA-PC-SD)的体外溶出以及体内药动学规律,采用HPLC法考察CA-PC-SD的体外溶出,大鼠灌胃后测定其血药浓度,并采用DAS 2.0软件分析计算药动学参数.结果显示:CA-PC-SD显著改善绿原酸磷脂复合物(CA-PC)的溶出效果,相较于原料药(CA)其相对生物利用度提高2.12倍.表明CA-PC-SD能显著改善CA-PC的体外溶出特性以及CA的口服生物利用率.     

A novel osmotic pump-based controlled delivery system consisting of pH-modulated solid dispersion for poorly soluble drug flurbiprofen: in vitro and in vivo evaluation

Abstract

In this study, a novel controlled release osmotic pump capsule consisting of pH-modulated solid dispersion for poorly soluble drug flurbiprofen (FP) was developed to improve the solubility and oral bioavailability of FP and to minimize the fluctuation of plasma concentration. The pH-modulated solid dispersion containing FP, Kollidon® 12 PF and Na₂CO₃ at a weight ratio of 1/4.5/0.02 was prepared using the solvent evaporation method. The osmotic pump capsule was assembled by semi-permeable capsule shell of cellulose acetate (CA) prepared by the perfusion method. Then, the solid dispersion, penetration enhancer, and suspending agents were tableted and filled into the capsule. Central composite design-response surface methodology was used to evaluate the influence of factors on the responses. A second-order polynomial model and a multiple linear model were fitted to correlation coefficient of drug release profile and ultimate cumulative release in 12?h, respectively. The actual response values were in good accordance with the predicted ones. The optimized formulation showed a complete drug delivery and zero-order release rate. Beagle dogs were used to be conducted in the pharmacokinetic study. The in vivo study indicated that the relative bioavailability of the novel osmotic pump system was 133.99% compared with the commercial preparation. The novel controlled delivery system with combination of pH-modulated solid dispersion and osmotic pump system is not only a promising strategy to improve the solubility and oral bioavailability of poorly soluble ionizable drugs but also an effective way to reduce dosing frequency and minimize the plasma fluctuation.     

Application of scCO2 technology for preparing CoQ10 solid dispersion and SFC-MS/MS for analyzing in vivo bioavailability

Objective: In this study, solid dispersion (SD) for oral delivery of a poorly water-soluble drug, coenzyme Q10 was developed by supercritical fluid technology and characterized in vitro and in vivo.

Methods: Dissolution was used to optimize the formulations of CoQ10-SD. The physicochemical properties of SD were investigated by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and scanning electron microscopy (SEM). The supercritical fluid chromatography–electrospray ionization tandem mass spectrometry (SFC–ESI-MS/MS) was used for the in vivo study.

Results: The results of DSC and PXRD indicated that the drug in SD was in amorphous state. In vitro drug release, the dissolution of coenzyme Q10 in solid dispersion improved to 78.8% compared with commercial tablets of 0.16%. The area under c–t curve (AUC_0–72h) and mean maximum concentrations (C_max) of CoQ10-SD were 2.43-fold and 3.0-fold, respectively higher than that of commercial tablets in rats, confirming improved bioavailability.

Conclusion: Supercritical fluid technology was successfully used for the preparation and analysis of CoQ10-SD for the first time and significantly improved the dissolution and bioavailability of coenzyme Q10.     

In vitro and in vivo studies on a novel solid dispersion of repaglinide using polyvinylpyrrolidone as the carrier

In order to improve the dissolution and absorption of the water insoluble drug repaglinide, a solid dispersion was developed by solvent method using polyvinylpyrrolidone K30 (PVP K30) as the hydrophilic carrier for the first time. Studies indicated that both solubility and the dissolution rate of repaglinide were significantly increased in the solid dispersion system compared with that of repaglinide raw material or physical mixtures. The repaglinide solid dispersions with PVP K30 solid state was characterized by polarizing microscopy, differential scanning calorimetry (DSC), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FT-IR). DSC and XRD studies indicated that repaglinide existed in an amorphous form in the solid dispersion. FT-IR analysis demonstrated the presence of intermolecular hydrogen bonding between repaglinide and PVP K30 in the solid dispersion. In the in situ gastrointestinal perfusion experiment, solid dispersion was shown to remarkably enhance the absorption of repaglinide in stomach and all segments of intestine. In vivo pharmacokinetic study in rats showed that immediate and complete release of repaglinide from the solid dispersion resulted in rapid absorption that significantly increased the bioavailability and the maximum plasma concentration over repaglinide raw material. These results demonstrated PVP K30 was an appropriate carrier for solid dispersion of repaglinide, with increased dissolution and oral absorption.     

Effect of water-soluble polymers on the physical stability of aqueous polymeric dispersions and their implications on the drug release from coated pellets

Purpose: To investigate the physical stability and drug release-related properties of the aqueous polymer dispersions Kollicoat® SR 30 D and Aquacoat® ECD (an ethylcellulose-based dispersion) in the presence water-soluble polymers (pore formers) with special attention to the potential flocculation of the polymer dispersions. Methods: A precise characterization of the flocculation phenomena in undiluted samples was monitored with turbidimetric measurements using the Turbiscan Lab-Expert. Theophylline or propranolol HCl drug-layered pellets were coated with Kollicoat® SR 30 D and Aquacoat® ECD by the addition of water-soluble polymers polyvinyl pyrrolidone (Kollidon® 30 and 90 F), polyvinyl alcohol–polyethylene glycol graft copolymer (Kollicoat® IR), and hydroxypropyl methylcellulose (Pharmacoat® 603 or 606) in a fluidized bed coater Glatt GPCG-1 and drug release was performed according to UPS paddle method. Results: Stable dispersions were obtained with both Kollicoat® SR 30 D (a polyvinyl acetate-based dispersion) and Aquacoat® ECD with up to 50% hydrophilic pore formers polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat® IR) and polyvinyl pyrrolidone (Kollidon® 30). In general, Kollicoat® SR 30 D was more stable against flocculation than Aquacoat® ECD. Stable dispersions were also obtained with higher amounts of water-soluble polymer or by reducing the concentration of the polymer dispersion. Flocculated dispersions resulted in porous films and, thus, in a sharp increase in drug release. Conclusions: Kollicoat® SR 30 D was more resistant to flocculation upon addition of water-soluble polymers than Aquacoat® ECD. The continuous adjustment of drug release from Kollicoat® SR 30-coated pellets was possible with Kollicoat® IR amounts over a broad range.     

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.     

Corroboration of naringin effects on the intestinal absorption and pharmacokinetic behavior of candesartan cilexetil solid dispersions using in-situ rat models

Objective: The aim of this study was to corroborate the effects of naringin, a P-glycoprotein inhibitor, on the intestinal absorption and pharmacokinetics of candesartan (CDS) from candesartan cilexetil (CAN) solid dispersions using in-situ rat models.

Materials and methods: Intestinal transport and absorption studies were examined by in-situ single pass perfusion and closed-loop models. We evaluated the intestinal membrane damage in the presence of naringin by measuring the release of protein and alkaline phosphatase (ALP).

Results and discussion: We noticed 1.47-fold increase in P_eff of CDS from freeze-dried CAN-loaded solid dispersions with naringin (15?mg/kg, w/w) when compared with freeze-dried solid dispersion without naringin using in-situ single pass intestinal perfusion model. However, no intestinal membrane damage was observed in the presence of naringin. Our findings from in-situ closed-loop pharmacokinetic studies showed 1.34-fold increase in AUC with elevated C_max and shortened t_max for freeze-dried solid dispersion with naringin as compared to freeze-dried solid dispersion without naringin.

Conclusion: This study demonstrated that increased solubilization (favored by freeze-dried solid dispersion) and efflux pump inhibition (using naringin), the relative bioavailability of CDS can be increased, suggesting an alternative potential for improving oral bioavailability of CAN.     

Tailoring the release rates of fluconazole using solid dispersions in polymer blends

Formulations of the drug Fluconazole with different release characteristics were prepared by dispersing the active pharmaceutical ingredient (API) in various polymeric carriers, and especially in polymer blends. Fluconazole was tested as a model drug with low solubility in water. First solid dispersions in pure polymers were studied. Use of pure polyvinylpyrrolidone (PVP) as carrier even for high drug load (30 wt%) resulted in rapid release. The drug release rates decreased by increasing the API content. The dissolution rate enhancement was attributed to drug amorphization, particle size reduction, and possible improvement of the drug wetting characteristics. Hydroxypropyl methylcellulose (HPMC) gave solid dispersions, from which the release rates of the drug varied from immediate to sustaining. As the drug amount increased, the rates became higher. Similar behavior also was found when Chitosan was used as carrier, with much more controlled rates close to those for sustained release. These differences were mainly attributed to the limited solubility and swelling of HPMC and Chitosan in aquatic media. To study the effectiveness of polymer blends in adjusting the release rates of the drug, solid dispersions in PVP/HPMC and PVP/Chitosan miscible blends were studied. The release rates of Fluconazole were adequately adjusted by differentiating the weight ratio of the polymers in the blends. PVP/HPMC blends with high PVP content can be used for immediate release formulations but PVP/Chitosan blends are inappropriate for such formulations and can only be used for controlled release.     

Stabilizing ability of surfactant on physicochemical properties of drug nanoparticles generated from solid dispersions

This study was aimed to examine the nanoparticle formation from redispersion of binary and ternary solid dispersions. Binary systems are composed of various ratios of glibenclamide (GBM) and polyvinylpyrrolidone K30 (PVP-K30), whereas a constant amount at 2.5%w/w of a surfactant, sodium lauryl sulfate (SLS) or Gelucire44/14 (GLC), was added to create ternary systems. GBM nanoparticles were collected after the systems were dispersed in water for 15?min. The obtained nanoparticles were characterized for size distribution, crystallinity, thermal behavior, molecular structure, and dissolution properties. The results indicated that GBM nanoparticles could be formed when the drug content of the systems was lower than 30%w/w in binary systems and ternary systems containing SLS. The particle size ranged from 200 to 500?nm in diameter with narrow size distribution. The particle size was increased with increasing drug content in the systems. The obtained nanoparticles were spherical and showed the amorphous state. Furthermore, because of being amorphous form and reduced particle size, the dissolution of the generated nanoparticles was markedly improved compared with the GBM powder. In contrast, all the ternary solid dispersions prepared with GLC anomalously provided the crystalline particles with the size ranging over 5?µm and irregular shape. Interestingly, this was irrelevant to the drug content in the systems. These results indicated the ability of GLC to destabilize the polymer network surrounding the particles during particle precipitation. Therefore, this study suggested that drug content, quantity, and type of surfactant incorporated in solid dispersions drastically affected the physicochemical properties of the precipitated particles.