Cyclodextrin and phospholipid complexation in solubility and dissolution enhancement: a critical and meta-analysis

Introduction: Poor solubility and dissolution of drugs are the major challenges in drug formulation and delivery. In order to improve the solubility and dissolution profile of drugs, various methods have been investigated so far. The cyclodextrin (CD) complexation and phospholipid (PL) complexation are among the exhaustively investigated methods employed for more precise improvement of the solubility and dissolution of poorly water-soluble drugs.

Areas covered: The article discusses the CD and PL complexation techniques of solubility and dissolution enhancement. Various studies reporting the CD and PL complexation as the potential approaches to improve the dissolution, absorption and the bioavailability of the drugs have been discussed. The article critically reviews the physicochemical properties of CDs and PLs, eligibility of drugs for both the complexation, thermodynamics of complexation, methods of preparation, characterization, advantages, limitation and the meta-analysis of some studies for both the techniques.

Expert opinion: The CD and PL complexation techniques are very useful in improving solubility and dissolution (and hence the bioavailability) of biopharmaceutical classification system Class II and Class IV drugs. The selection of a particular kind of complexation can be made on the basis of eligibility criteria (of drugs) for the individual techniques, cost, stability and effectiveness of the complexes.     

Effects of aqueous solubility and dissolution characteristics on oral bioavailability of entacapone

Entacapone is a new catechol‐O‐methyltransferase (COMT) inhibitor used clinically in a triple combination therapy for Parkinson's disease (PD). The bioavailability of entacapone after oral administration is low and subject to large interindividual variation. The purpose of this study was to evaluate aqueous solubility/dissolution profiles of entacapone in vitro, and to evaluate their role in the poor oral bioavailability of entacapone in rats. The effect of the novel pharmaceutical excipient hydroxypropyl‐β‐cyclodextrin (HP‐β‐CD) on the aqueous solubility and dissolution of entacapone, and on entacapone bioavailability in rats, was also studied. The aqueous solubility of entacapone determined in this study is below 80 μg/ml at pH ≤5.0 and increases with increased pH. Due to its poor aqueous solubility, the dissolution of entacapone in an acidic environment is very slow. Complexation of entacapone with HP‐β‐CD (10% [w/v]) increases the aqueous solubility of entacapone 12‐fold and 85‐fold at pH 3.0 and at pH 5.0, respectively, and improves its bioavailability at the former pH about 2‐fold, compared to an entacapone suspension at that pH. The administration of entacapone as a pH 7.4 solution further increases the absolute bioavailability of entacapone, which is 1.8 and 3.3 times higher compared to the inclusion complex or suspension, respectively. In conclusion, it is possible to increase entacapone's bioavailability by improving its solubility and dissolution properties. However, the solubility and dissolution properties of entacapone do not fully explain its erratic bioavailability. Drug Dev. Res. 49:238–244, 2000. © 2000 Wiley‐Liss, Inc.     

共无定形技术改善葛根素水溶性及增溶机制研究

葛根素(PUE)为异黄酮类成分,具有广泛的药理活性,但其低水溶性限制了其口服固体制剂的开发.本研究以烟酰胺(NIC)为配体通过减压旋蒸法制备了PUE-NIC共无定形体系,同时联合粉末X-射线衍射(PXRD)、差示扫描量热法(DSC)和红外光谱(FT-IR)等多种手段对其进行表征,并对其溶出行为及增溶机制进行了系统的研究...     

Overcoming sink limitations in dissolution testing: a review of traditional methods and the potential utility of biphasic systems

Objectives The conventional dissolution test, particularly the USP apparatus I and II, remains an important tool in the armory of the pharmaceutical development scientist. For realistic dissolution characterization, sink conditions, where saturation solubility of a drug in the dissolution medium is at least three times more than the drug concentration, are critical. These conditions can be problematic to maintain with formulations containing poorly‐soluble actives. This review summarizes the role of the dissolution test in the pharmaceutical industry, together with some traditional techniques/additives used to enhance solubility and facilitate the achievement of sink conditions. The biphasic dissolution system, an innovative model for the treatment of poorly‐soluble species, will also be discussed. Key findings The biphasic dissolution model utilizes media comprising immiscible aqueous and organic layers whereby the drug, following initial aqueous dissolution, partitions into the organic layer. This step, which acts to remove all dissolved species from the aqueous layer, enables further aqueous dissolution to occur and hence the dissolution–partition cycle continues. Crucially, the aqueous layer does not saturate allowing sink conditions to be maintained and hence the experiment will, in theory, yield complete dissolution. Summary This review highlights important concepts regarding solubility/sink limitation and intends to provoke debate among analytical and formulation scientists as to the potential advantages, long‐term development and widespread implementation of a biphasic dissolution system in drug development.     

Synthesis of an iodine‐123‐labeled celecoxib analogue: a potential spect agent

Celecoxib (4‐[5‐(4‐methylphenyl)‐3‐(trifluoromethyl)‐1H‐pyrazol‐1yl]‐benzenesulfonamide) is an effective inhibitor of the cyclooxygenase‐2 (COX‐2). The synthesis of a no‐carrier‐added iodine‐123‐labeled analogue of celecoxib was accomplished in four steps for potential use in single photon tomography. Copyright © 2005 John Wiley & Sons, Ltd.     

Caffeine pretreatment: enhancement and attenuation of d-amphetamine-induced activity

Caffeine pretreatment was studied for its effects on d-amphetamine-induced locomotor activity. Caffeine (30 mg/kg) was given either simultaneously with or at one of several intervals (0.5, 1.5, 4.5, 12, and 13.5 hours) before d-amphetamine (1.5 mg/kg). Enhancement of d-amphetamine activity occurred with simultaneous and 30 min caffeine pretreatment. However, when given 12 or 13.5 hours before d-amphetamine, caffeine diminished the activity, measured in stabilimeter cages. Several doses of caffeine (7.5, 15, 30, and 60 mg/kg) were given in multiple treatments ending 12 hours before d-amphetamine (1.5 mg/kg) to determine the effective doses for attenuation of d-amphetamine-induced activity. Only 30 and 60 mg caffeine doses reduced d-amphetamine activity while also interfering with body weight gain.     

Evaluation of the losartan solubility in the biowaiver context by shake-flask method and intrinsic dissolution

This study aimed at evaluating the shake-flask use as a universal method to evaluate drug solubility in a biowaiver context as proposed by FDA, EMA and ANVISA. The solubility of losartan was determined in three buffers using the shake-flask method, intrinsic dissolution (ID) and Quantum Chemistry. Moreover, the evaluation of a losartan dissolution profile from coated tablets was conducted. The losartan low solubility in pH 1.2 and high solubility in pH 6.8 were observed using the shake-flask method. However, the solubility results using ID demonstrated its high solubility in pH 1.2 and 6.8. It was not possible to find conclusive results regarding the solubility of the drug in pH 4.5. The studies conducted by Quantum Chemistry provide molecular and electronic data that helped understand the losartan solvation in different pH values. Our experimental results defined that losartan can be classified as a low-solubility drug. In addition, this work shows that shake-flask cannot be a universal method of solubility studies in biowaiver context. Individual analysis will be necessary. The intrinsic dissolution should be considered as a complementary method.     

Improvement of solubility,dissolution and stability profile of artemether solid dispersions and self emulsified solid dispersions by solvent evaporation method

Abstract

The purpose of this study was to investigate changes in the water solubility of artemether; a poorly soluble drug used for the treatment of malaria. Different solid dispersions (SDs) of artemether were prepared using artemether and polyethylene glycol 6000 at ratio 12:88 (Group 1), self-emulsified solid dispersions (SESDs) containing artemether, polyethylene glycol 6000, cremophor-A-25, olive oil, hydroxypropylmethylcellulose and transcutol in the ratio 12:75:5:4:2:2, respectively (Group 2). SESDs were also prepared by substituting cremophor-A-25 in Group 2 with poloxamer 188 (noted as Group 3). Each of these preparations was formulated using physical mixing and the solvent evaporation method. Aqueous solubility of artemether improved 11-, 95- and 102-fold, while dissolution (in simulated gastric fluid) increased 3-, 13- and 14-fold, for formulation groups 1, 2 and 3, respectively. X-ray diffraction patterns of SDs indicated a decrease in peak intensities at 10° implying reduced artemether crystallinity. Scanning electron micrographs invariably revealed embedment of artemether by various excipients and a glassy appearance for solvent evaporated mixtures for all three formulation Groups. Our findings indicate improved hydrophilic interactions for drug particles yield greater solubility and dissolution in the following order for artemether formulating methods: solvent evaporation mixtures?>?physical mixtures?>?pure artemether.     

β-cyclodextrin complexes of celecoxib: Molecular-modeling, characterization, and dissolution studies

Celecoxib, a specific inhibitor of cycloxygenase-2 (COX-2) is a poorly water-soluble nonsteroidal anti-inflammatory drug with relatively low bioavailability. The effect of beta-cyclodextrin on the aqueous solubility and dissolution rate of celecoxib was investigated. The possibility of molecular arrangement of inclusion complexes of celecoxib and beta-cyclodextrin were studied using molecular modeling and structural designing. The results offer a better correlation in terms of orientation of celecoxib inside the cyclodextrin cavity. Phase-solubility profile indicated that the solubility of celecoxib was significantly increased in the presence of beta-cyclodextrin and was classified as AL-type, indicating the 1:1 stoichiometric inclusion complexes. Solid complexes prepared by freeze drying, evaporation, and kneading methods were characterized using differential scanning calorimetry, powder x-ray diffractometry, and scanning electron microscopy. In vitro studies showed that the solubility and dissolution rate of celecoxib were significantly improved by complexation with beta-cyclodextrin with respect to the drug alone. In contrast, freeze-dried complexes showed higher dissolution rate than the other complexes.     

Improving glyburide solubility and dissolution by complexation with hydroxybutenyl‐β‐cyclodextrin

Objectives Glyburide, an important drug for type 2 diabetes, has extremely poor aqueous solubility and resulting low bioavailability. This study describes the ability of hydroxybutenyl‐β‐cyclodextrin (HBenBCD) to form complexes with glyburide, with enhanced solubility and dissolution rate in vitro. Method Glyburide and glyburide‐HBenBCD were evaluated in various test media known to simulate human gastrointestinal conditions in the fasted and fed states, respectively. Key findings At ～14 wt% drug load, in the presence of HBenBCD, an almost 400‐fold increase in glyburide aqueous solubility was observed. In the presence of HBenBCD, glyburide solubility was also significantly improved in all physiologically relevant test media. Subsequent dissolution experiments confirmed the solubility study results; the dissolution rate and total amount of drug released were significantly increased. Conclusions Complexation with HBenBCD may be an effective way to increase the bioavailability of glyburide.     

Mesoporous silica formulation strategies for drug dissolution enhancement: a review

Introduction: Silica materials, in particular mesoporous silicas, have demonstrated excellent properties to enhance the oral bioavailability of poorly water-soluble drugs. Current research in this area is focused on investigating the kinetic profile of drug release from these carriers and manufacturing approaches to scale-up production for commercial manufacture.

Areas covered: This review provides an overview of different methods utilized to load drugs onto mesoporous silica carriers. The influence of silica properties and silica pore architecture on drug loading and release are discussed. The kinetics of drug release from mesoporous silica systems is examined and the manufacturability and stability of these formulations are reviewed. Finally, the future prospects of mesoporous silica drug delivery systems are considered.

Expert opinion: Substantial progress has been made in the characterization and development of mesoporous drug delivery systems for drug dissolution enhancement. However, more research is required to fully understand the drug release kinetic profile from mesoporous silica materials. Incomplete drug release from the carrier and the possibility of drug re-adsorption onto the silica surface need to be investigated. Issues to be addressed include the manufacturability and regulation status of formulation approaches employing mesoporous silica to enhance drug dissolution. While more research is needed to support the move of this technology from the bench to a commercial medicinal product, it is a realistic prospect for the near future.     

Kinetic solubility and dissolution velocity of rutin nanocrystals

Lyophilized rutin nanocrystals were intensively evaluated regarding their physicochemical properties with respect to particle size analyses, crystallinity, kinetic solubility and dissolution behavior. The particle size was determined by photon correlation spectroscopy (PCS) and laser diffraction (LD). DSC and X-ray diffraction were used to study the crystalline state of rutin nanocrystals. In a period of 1 week, the kinetic solubility was determined using a shaker at 25 °C. DSC and X-ray diffraction analyses showed that lyophilized rutin nanocrystals prepared by high pressure homogenization remained in crystalline state. Lyophilized rutin nanocrystals could be re-dispersed completely in water and the kinetic solubility in water increased to 133 μg/ml.. Lyophilized rutin nanocrystals were almost completely dissolved within 15 min in water, buffer of pH 1.2 and buffer of pH 6.8. In contrast, only 70% of rutin raw material (rutin microcrystals) was dissolved within 15 min. The superior physicochemical properties of rutin nanocrystals should overcome the absorption problem in the gastrointestinal tract and increase the bioavailability.     

A novel approach for predicting the dissolution profiles of pharmaceutical tablets

In this paper, the intrinsic dissolution profiles of naproxen (NAP) at pH values of 1.5 and 3.0 and of trimethoprim (TMP) at pH values of 1.5, 3.0, 5.0, 6.5 and 7.2 were measured. Meanwhile, the dissolution profiles of NAP and TMP from cylindrical tablets were measured at different temperatures (298.15 K, 305.15 K, 301.15 K and 310.15 K) and stirring speeds (50 rpm, 100 rpm and 150 rpm) as well as at different pH values (1.5, 3.0, 5.0, 6.5 and 7.2). Additionally the pH-dependent solubilities of both APIs were measured and modeled. The chemical-potential-gradient model combined with the perturbed-chain statistical associating fluid theory (PC-SAFT) was applied to predict the dissolution profiles of the cylindrical tablets of NAP and TMP under different conditions based on the analysis of their intrinsic dissolution profiles as well as on the determination of the surface-area reduction of the API tablets during dissolution. It was shown that the predicted dissolution profiles of the tablets under different conditions were in a good accordance with the experimental findings.     

Surfactant-mediated dissolution: contributions of solubility enhancement and relatively low micelle diffusivity

The objective of this study was to assess the contributions of surfactant-mediated solubility and micellar diffusivity on the ability of surfactant to enhance drug dissolution. The following model was derived to predict the degree to which surfactants enhance griseofulvin dissolution: phi = 1 + (fm/ff).((D(D-M)2/3)/(DD2/3)) where phi is the degree of surfactant-mediated dissolution enhancement, fm is the fraction of the drug in micelle, and ff is the fraction of free drug, and DD and D(D-M) are the diffusivities of free drug and drug-loaded micelles, respectively. The Wood apparatus was used to measure the dissolution of griseofluvin in the presence of the anionic surfactant sodium dodecyl sulfate (SDS), the cationic surfactant cetyl trimethyl ammonium bromide (CTAB), and the neutral surfactants Tween 80 and Cremophor EL. DD was estimated using the Levich equation. D(D-M) was measured using dynamic light scattering. Griseofulvin solubility was evaluated in SDS, CTAB, Tween 80, and Cremophor EL at the surfactant concentrations used in the dissolution studies. DD was 11.0 x 10(-6) cm2/s. D(D-M) was 1.29 x 10(-6) cm2/s, 0.956 x 10(-6) cm2/s, 0.569 x 10(-6) cm2/s, and 0.404 x 10(-6) cm2/s for griseofulvin-loaded micelles of SDS, CTAB, Tween 80, and Cremophor EL, respectively. At the highest surfactant concentrations studied, griseofulvin solubility increased 107-fold, 31-fold, fourfold, and threefold for SDS, CTAB, Tween 80, and Cremophor EL. Dissolution into SDS and CTAB were markedly enhanced, but only about one-third as much as solubility enhancement. Dissolution enhancement in the presence of SDS and CTAB were in excellent agreement with model predicted values, with prediction error less than 12%. The model predicted dissolution into Tween 80 and Cremophor EL to be minimally enhanced, as was observed, although the model underpredicted dissolution into these two neutral surfactants. The derived model predicted surfactant-mediated dissolution and reflects dissolution enhancement to be promoted by surfactant-enhanced solubility, but limited by the relatively slow diffusion of drug-loaded surfactant micelles.     

Spherical crystals of celecoxib to improve solubility, dissolution rate and micromeritic properties

Celecoxib spherical agglomerates were prepared with polyvinylpyrrolidone (PVP) using acetone, water and chloroform as solvent, non-solvent and bridging liquid, respectively. The agglomerates were characterized by differential scanning calorimetry (DSC), X-ray diffraction (XRD), IR spectroscopic studies and scanning electron microscopy (SEM). The IR spectroscopy and DSC results indicated the absence of any interactions between drug and additives. XRD studies showed a decrease in crystallinity in agglomerates. The crystals exhibited significantly improved micromeritic properties compared to pure drug. The loading efficiency (% or mg drug per 100 mg crystals) was in the range of 93.9 +/- 2.3 and 97.3 +/- 1.3% (n = 3) with all formulations. The aqueous solubility and dissolution rate of the drug from crystals was significantly (p < 0.05) increased (nearly two times). The solubility and in vitro drug release rates increased with an increase in PVP concentration (from 2.5 to 10%). The SEM studies showed that the crystal posseses a good spherical shape with smooth and regular surface.     

Liquisolid technology for dissolution rate enhancement or sustained release

Importance of the field: Most of the drugs that have been invented are of BCS Class II. Therefore, dissolution rate enhancement is the key aspect for absorption of these drugs. Liquisolid technology is very efficient in the dissolution rate enhancement of these drugs. Moreover, use of other polymers such as Eudragit and hydroxypropyl methylcellulose in the liquisolid approach can cause sustained release of drugs. This review focuses on the formulation approaches of liquisolid tablets or compacts along with its fundamental principles.

Areas covered in this review: The review focuses on the developments in liquisolid technology from 1998 to 2009 with in vitro and in vivo performance of the dosage forms prepared using this technology.

What the reader will gain: Benefits of this review include a concise evaluation of this technology by focusing on the scope of future developments to be done using this technique.

Take home message: Liquisolid technology, the next generation of powder solution technology, can be helpful for enhancing dissolution rates of poorly water-soluble drugs as well as effective at sustaining drug release.     

Preparation and characterization of nanocrystals for solubility and dissolution rate enhancement of nifedipine

Poorly water-soluble drugs such as nifedipine (NIF) (approximately 20 microg/ml) offer challenging problems in drug formulation as poor solubility is generally associated to poor dissolution characteristics and thus to poor oral bioavailability. In order to enhance these characteristics, preparation of nifedipine nanoparticles has been achieved using high pressure homogenization. The homogenization procedure has first been optimized in regard to particle size and size distribution. Nanoparticles were characterized in terms of size, morphology and redispersion characteristics following water-removal. Saturation solubility and dissolution characteristics were investigated and compared to the un-milled commercial NIF to verify the theoretical hypothesis on the benefit of increased surface area. Crystalline state evaluation before and following particle size reduction was also conducted through differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) to denote eventual transformation to amorphous state during the homogenization process. Through this study, it has been shown that initial crystalline state is maintained following particle size reduction and that the dissolution characteristics of nifedipine nanoparticles were significantly increased in regards to the commercial product. The method being simple and easily scaled up, this approach should have a general applicability to many poorly water-soluble drug entities.     

Directly compressed rosuvastatin calcium tablets that offer hydrotropic and micellar solubilization for improved dissolution rate and extent of drug release

The objective was to use caffeine and Soluplus® to improve the dissolution rate and to maintain a concentration of BCS Class II rosuvastatin calcium that exceeds its solubility. Caffeine and Soluplus® together substantially improved the dissolution rate and the extent of rosuvastatin release. Formulations for direct compression tablets included Formulation F1, a control with drug but with neither caffeine nor Soluplus® present; F2 with drug-caffeine complex; F3 with drug and Soluplus® and F4 with drug-caffeine complex and Soluplus®. Each formulation blend provided satisfactory flow properties. Tablets were comparable in mass, hardness and friability. A marked decrease in disintegration time occurred when the hydrotropic or micellar agent was included in the formulation. Assay (98–100%) and content uniformity (99–100%) results met requirements. Release studies in pH 1.2, 6.6, and 6.8 buffers revealed the superiority of F4. At 45 min sampling time, F3 and F4 tablets each provided a cumulative drug release greater than 70% in each medium. F2 tablets exhibited compliance to official standards in pH 6.6 and 6.8 buffers but not in pH 1.2 buffer, whereas tablets based on F1 failed in each medium. Two-factor ANOVA of the release data revealed a statistical difference across the four formulations in each release medium. Pairwise comparison of release profiles demonstrated that, of the four formulations, F4 provided the most effectively enhanced dissolution rate, improvement to the extent of drug release and support of a concentration higher than the solubility of rosuvastatin calcium.     

Preparation and evaluation of itraconazole dihydrochloride for the solubility and dissolution rate enhancement

The purpose of this work was to explore the feasibility of preparing itraconazole hydrochloride to improve the solubility and dissolution rate. Itraconazole dihydrochloride was synthesized by bubbling anhydrous hydrogen chloride gas into the acetone suspension of itraconazole. Results of the elementary analysis gave the molecular formula of C(35)H(38)Cl(2)N(8)O(4).2HCl and its structure was confirmed by Fourier transform infrared (FTIR), thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). Powder X-Ray diffraction (PXRD) suggested that a new crystalline form of the salt was formed. The morphology and mean size distribution study by scanning electron microscopy (SEM) and dynamic light scattering (DLS) confirmed that the salt was dispersable nanoparticle aggregation. Aqueous solubility measurements showed that the solubility of the salt, its 1:1, 1:2 and 1:3 (w/w) physical mixtures with beta-cyclodextrin (beta-CD) was 6, 99, 236 and 388 times greater than itraconazole. More than 94% of itraconazole was dissolved out of the salt/beta-CD 1/3 physical mixture after 60min. The stability studies indicated that the physical mixture remained stable for 24 months in assay, the related substances and dissolution. Based on the present results, it is concluded that hydrochloride formation can significantly increase solubility and dissolution rate of itraconazole, and the formulation of itraconazole dihydrochloride/beta-CD (1/3) would be an environment-friendly, economic and practical alternative to the commercially available itraconazole capsules (Sporanox)