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Topical Collection "Poorly Soluble Drugs"

A topical collection in Molecules (ISSN 1420-3049). This collection belongs to the section "Medicinal Chemistry".

Editors

Collection Editor
Prof. Dr. Guy Van den Mooter

Drug Delivery and Disposition, KU Leuven, Leuven, Belgium
Website | E-Mail
Interests: Amorphous solid dispersions, nanocrystals, mesoporous silica, thermal analysis, solid state analysis, spray drying, bead coating
Collection Editor
Prof. Dr. Holger Grohganz

Department of Pharmacy University of Copenhagen, Denmark
Website | E-Mail
Interests: freeze-drying and spray-drying; co-amorphous systems; design of experiments, process analytical technology and quality by design; peptides and proteins in pharmaceutical formulations
Collection Editor
Prof. Dr. Korbinian Löbmann

Department of Pharmacy University of Copenhagen, Denmark
Website | E-Mail
Interests: amorphous drugs and formulations; co-amorphous drug delivery; silica based drug delivery systems; functional excipients
Former Guest Editor
Prof. Dr. Thomas Rades

Reseach Chair in Pharmaceutical Design and Drug Delivery Faculty of Health and Medical Sciences, Department of Pharmacy, University of Copenhagen, Universitetsparken 2, 2100 København Ø, Denmark
Website | E-Mail
Interests: the solid state of drugs and dosage forms; poorly water soluble drugs; amorphous drugs and drug delivery systems; lipid based drug delivery systems; analytical techniques in the solid state

Topical Collection Information

Dear Colleagues,

Increasingly important bottlenecks for the development of medicines result from the poor aqueous solubilities and low dissolution rates of many small molecular weight drugs in the pipelines of pharmaceutical companies. To increase the solubilities and dissolution rates of drugs, and thus their bioavailabilities, several feasible approaches can be taken, and are of special interest, both in academia, and in the pharmaceutical industry. These include the conversion of crystalline drugs to their respective amorphous forms, the use of lipid based drug delivery systems, particle size reduction, salt-, co-crystal, and pro-drug formations, and the use of cyclodextrin complexes, to name but a few. This Special Issue aims to provide a forum for the dissemination of the latest information on new approaches and methods for dealing with poorly soluble drugs, and with methods of testing their success.

Prof. Dr. Korbinian Löbmann
Prof. Dr. Holger Grohganz
Prof. Dr. Guy Van den Mooter
Collection Editors

Manuscript Submission Information

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Keywords

  • solubility
  • dissolution rate
  • amorphous systems
  • lipid based drug delivery systems
  • nanoparticles/nanocrystals
  • cyclodextrins
  • co-crystals
  • salts
  • prodrugs
  • complexes
  • supersaturation

Published Papers (24 papers)

2017

Jump to: 2016, 2015

Open AccessArticle Application of Soluplus to Improve the Flowability and Dissolution of Baicalein Phospholipid Complex
Molecules 2017, 22(5), 776; doi:10.3390/molecules22050776
Received: 29 March 2017 / Revised: 3 May 2017 / Accepted: 8 May 2017 / Published: 11 May 2017
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Abstract
In this study, a novel ternary complex system (TCS) composed of baicalein, phospholipids, and Soluplus was prepared to improve the flowability and dissolution for baicalein phospholipid complex (BPC). TCS was characterized using differential scanning calorimetry (DSC), infrared spectroscopy (IR), powder X-ray diffraction (PXRD),
[...] Read more.
In this study, a novel ternary complex system (TCS) composed of baicalein, phospholipids, and Soluplus was prepared to improve the flowability and dissolution for baicalein phospholipid complex (BPC). TCS was characterized using differential scanning calorimetry (DSC), infrared spectroscopy (IR), powder X-ray diffraction (PXRD), and scanning electron microscopy (SEM). The flowability, solubility, oil–water partition coefficient, in vitro dissolution, and in vivo pharmacokinetics of the system were also evaluated. DSC, IR, PXRD, and SEM data confirmed that the crystal form of baicalein disappeared in BPC and TCS. Furthermore, the angle of repose of TCS of 35° indicated an improvement in flowability, and solubility increased by approximately eight-fold in distilled water when TCS was compared with BPC (41.00 ± 4.89 μg/mL vs. 5.00 ± 0.16 μg/mL). Approximately 91.24% of TCS was released at the end of 60 min in 0.5% SDS (pH = 6.8), which suggested that TCS could improve the dissolution velocity and extent. Moreover, TCS exhibited a considerable enhancement in bioavailability with higher peak plasma concentration (25.55 μg/mL vs. 6.05 μg/mL) and increased AUC0–∞ (62.47 μg·h/mL vs. 50.48 μg·h/mL) with 123.75% relative bioavailability compared with BPC. Thus, Soluplus achieved the purpose of improving the flowability and solubility of baicalein phospholipid complexes. The application of Soluplus to phospholipid complexes has great potential. Full article
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Figure 1

Open AccessArticle Amorphous-Amorphous Phase Separation in API/Polymer Formulations
Molecules 2017, 22(2), 296; doi:10.3390/molecules22020296
Received: 22 December 2016 / Revised: 8 February 2017 / Accepted: 9 February 2017 / Published: 15 February 2017
PDF Full-text (3980 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The long-term stability of pharmaceutical formulations of poorly-soluble drugs in polymers determines their bioavailability and therapeutic applicability. However, these formulations do not only often tend to crystallize during storage, but also tend to undergo unwanted amorphous-amorphous phase separations (APS). Whereas the crystallization behavior
[...] Read more.
The long-term stability of pharmaceutical formulations of poorly-soluble drugs in polymers determines their bioavailability and therapeutic applicability. However, these formulations do not only often tend to crystallize during storage, but also tend to undergo unwanted amorphous-amorphous phase separations (APS). Whereas the crystallization behavior of APIs in polymers has been measured and modeled during the last years, the APS phenomenon is still poorly understood. In this study, the crystallization behavior, APS, and glass-transition temperatures formulations of ibuprofen and felodipine in polymeric PLGA excipients exhibiting different ratios of lactic acid and glycolic acid monomers in the PLGA chain were investigated by means of hot-stage microscopy and DSC. APS and recrystallization was observed in ibuprofen/PLGA formulations, while only recrystallization occurred in felodipine/PLGA formulations. Based on a successful modeling of the crystallization behavior using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT), the occurrence of APS was predicted in agreement with experimental findings. Full article
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Open AccessCommunication Poloxamer-Based Thermoreversible Gel for Topical Delivery of Emodin: Influence of P407 and P188 on Solubility of Emodin and Its Application in Cellular Activity Screening
Molecules 2017, 22(2), 246; doi:10.3390/molecules22020246
Received: 27 December 2016 / Revised: 29 January 2017 / Accepted: 2 February 2017 / Published: 7 February 2017
PDF Full-text (2839 KB) | HTML Full-text | XML Full-text
Abstract
Emodin is a component in a Chinese herb, Rheum officinale Baill, traditionally used for diabetes and anticancer. Its poor solubility is one of the major challenges to pharmaceutical scientists. We previously reported on thermoreversible gel formulations based on poloxamer for the topical delivery
[...] Read more.
Emodin is a component in a Chinese herb, Rheum officinale Baill, traditionally used for diabetes and anticancer. Its poor solubility is one of the major challenges to pharmaceutical scientists. We previously reported on thermoreversible gel formulations based on poloxamer for the topical delivery of emodin. The present study was to understand the effect of poloxamer type on emodin solubility and its application in cellular activity screening. Various gel formulations composed of poloxamer 407 (P407), poloxamer 188 (P188) and PEG400 were prepared and evaluated. Major evaluation parameters were the gelation temperature (Tgel) and solubility of emodin. The emodin solubility increased with increasing poloxamer concentration and the Tgel was modulated by the proper combination of P407. In particular, this study showed that the amount of P407 in thermoreversible poloxamer gel (PG) was the dominant factor in enhancing solubility and P188 was effective at fixing gelation temperature in the desired range. A thermoreversible emodin PG was selected as the proper composition with the liquid state at room temperature and gel state at body temperature. The gel showed the solubility enhancement of emodin at least 100-fold compared to 10% ethanol or water. The thermoreversible formulation was applied for in vitro cellular activity screening in the human dermal fibroblast cell line and DLD-1 colon cancer cell line after dilution with cell culture media. The thermoreversible gel formulation remained as a clear solution in the microplate, which allowed reliable cellular activity screening. In contrast, emodin solution in ethanol or DMSO showed precipitation at the corresponding emodin concentration, complicating data interpretation. In conclusion, the gel formulation is proposed as a useful prototype topical formulation for testing emodin in vivo as well as in vitro. Full article
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2016

Jump to: 2017, 2015

Open AccessArticle Long-Term Stability of New Co-Amorphous Drug Binary Systems: Study of Glass Transitions as a Function of Composition and Shelf Time
Molecules 2016, 21(12), 1712; doi:10.3390/molecules21121712
Received: 24 October 2016 / Revised: 29 November 2016 / Accepted: 7 December 2016 / Published: 14 December 2016
PDF Full-text (722 KB) | HTML Full-text | XML Full-text
Abstract
The amorphous state is of particular interest in the pharmaceutical industry due to the higher solubility that amorphous active pharmaceutical ingredients show compared to their respective crystalline forms. Due to their thermodynamic instability, drugs in the amorphous state tend to recrystallize; in order
[...] Read more.
The amorphous state is of particular interest in the pharmaceutical industry due to the higher solubility that amorphous active pharmaceutical ingredients show compared to their respective crystalline forms. Due to their thermodynamic instability, drugs in the amorphous state tend to recrystallize; in order to avoid crystallization, it has been a common strategy to add a second component to hinder the crystalline state and form a thermally stable co-amorphous system, that is to say, an amorphous binary system which retains its amorphous structure. The second component can be a small molecule excipient (such as a sugar or an aminoacid) or a second drug, with the advantage that a second active pharmaceutical ingredient could be used for complementary or combined therapeutic purposes. In most cases, the compositions studied are limited to 1:1, 2:1 and 1:2 molar ratios, leaving a gap of information about phase transitions and stability on the amorphous state in a wider range of compositions. In the present work, a study of novel co–amorphous formulations in which the selection of the active pharmaceutical ingredients was made according to the therapeutic effect is presented. Resistance against crystallization and behavior of glass transition temperature ( T g were studied through calorimetric measurements as a function of composition and shelf time. It was found that binary formulations with T g temperatures higher than those of pure components presented long-term thermal stability. In addition, significant increments of T g values, of as much as 15 C, were detected as a result of glass relaxation at room temperature during storage time; this behavior of glass transition has not been previously reported for co-amorphous drugs. Based on these results, it can be concluded that monitoring behavior of T g and relaxation processes during the first weeks of storage leads to a more objective evaluation of the thermomechanical stability of an amorphous formulation. Full article
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Figure 1

Open AccessArticle Characterization, in Vivo and in Vitro Evaluation of Solid Dispersion of Curcumin Containing d-α-Tocopheryl Polyethylene Glycol 1000 Succinate and Mannitol
Molecules 2016, 21(10), 1386; doi:10.3390/molecules21101386
Received: 12 September 2016 / Accepted: 12 October 2016 / Published: 17 October 2016
PDF Full-text (3991 KB) | HTML Full-text | XML Full-text
Abstract
The aim of this study was to prepare a solid dispersion formulation of curcumin to enhance its solubility, dissolution rate, and oral bioavailability. The formulation was prepared with d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and mannitol using solvent evaporation and freeze-drying methods,
[...] Read more.
The aim of this study was to prepare a solid dispersion formulation of curcumin to enhance its solubility, dissolution rate, and oral bioavailability. The formulation was prepared with d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and mannitol using solvent evaporation and freeze-drying methods, which yielded a solid dispersion composed of curcumin, TPGS, and mannitol at a ratio of 1:10:15 (w/w/w). The solubility and dissolution rate of the curcumin solid dispersion markedly improved compared with those of curcumin powder and a physical mixture of curcumin, TPGS, and mannitol. About 90% of the curcumin was released from the solid dispersion formulation within 10 min. After administering the formulation orally to rats, higher plasma concentrations of curcumin were observed, with increases in the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of 86- and 65-fold, respectively, compared with those of curcumin powder. The solid dispersion formulation effectively increased intestinal permeability and inhibited P-gp function. These effects increased the anti-proliferative effect of curcumin in MDA-MB-231 breast cancer cells. Moreover, 2 h incubation with curcumin powder, solid dispersion formulation, and its physical mixture resulted in differential cytotoxic effect of paclitaxel in P-gp overexpressed LLC-PK1-P-gp and MDA-MB-231 cells through the inhibition of P-gp-mediated paclitaxel efflux. In conclusion, compared with curcumin, a solid dispersion formulation of curcumin with TPGS and mannitol could be a promising option for enhancing the oral bioavailability and efficacy of curcumin through increased solubility, dissolution rate, cell permeability, and P-gp modulation. Full article
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Open AccessArticle Positively Charged Nanostructured Lipid Carriers and Their Effect on the Dissolution of Poorly Soluble Drugs
Molecules 2016, 21(5), 672; doi:10.3390/molecules21050672
Received: 6 March 2016 / Revised: 11 May 2016 / Accepted: 17 May 2016 / Published: 20 May 2016
Cited by 1 | PDF Full-text (2328 KB) | HTML Full-text | XML Full-text
Abstract
The objective of this study is to develop suitable formulations to improve the dissolution rate of poorly water soluble drugs. We selected lipid-based formulation as a drug carrier and modified the surface using positively charged chitosan derivative (HTCC) to increase its water solubility
[...] Read more.
The objective of this study is to develop suitable formulations to improve the dissolution rate of poorly water soluble drugs. We selected lipid-based formulation as a drug carrier and modified the surface using positively charged chitosan derivative (HTCC) to increase its water solubility and bioavailability. Chitosan and HTCC-coated lipid particles had higher zeta-potential values than uncoated one over the whole pH ranges and improved encapsulation efficiency. In vitro drug release showed that all NLC formulations showed higher in vitro release efficiency than drug particle at pH 7.4. Furthermore, NLC formulation prepared with chitosan or HTCC represented good sustained release property. The results indicate that chitosan and HTCC can be excellent formulating excipients of lipid-based delivery carrier for improving poorly water soluble drug delivery. Full article

2015

Jump to: 2017, 2016

Open AccessReview The Prodrug Approach: A Successful Tool for Improving Drug Solubility
Molecules 2016, 21(1), 42; doi:10.3390/molecules21010042
Received: 14 October 2015 / Revised: 10 December 2015 / Accepted: 15 December 2015 / Published: 29 December 2015
Cited by 4 | PDF Full-text (10816 KB) | HTML Full-text | XML Full-text
Abstract
Prodrug design is a widely known molecular modification strategy that aims to optimize the physicochemical and pharmacological properties of drugs to improve their solubility and pharmacokinetic features and decrease their toxicity. A lack of solubility is one of the main obstacles to drug
[...] Read more.
Prodrug design is a widely known molecular modification strategy that aims to optimize the physicochemical and pharmacological properties of drugs to improve their solubility and pharmacokinetic features and decrease their toxicity. A lack of solubility is one of the main obstacles to drug development. This review aims to describe recent advances in the improvement of solubility via the prodrug approach. The main chemical carriers and examples of successful strategies will be discussed, highlighting the advances of this field in the last ten years. Full article
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Open AccessReview Understanding Critical Quality Attributes for Nanocrystals from Preparation to Delivery
Molecules 2015, 20(12), 22286-22300; doi:10.3390/molecules201219851
Received: 6 October 2015 / Revised: 8 December 2015 / Accepted: 8 December 2015 / Published: 12 December 2015
Cited by 3 | PDF Full-text (1740 KB) | HTML Full-text | XML Full-text
Abstract
Poor solubility of active pharmaceutical ingredients (APIs) is a great challenge for the pharmaceutical industry and, hence, drug nanocrystals are widely studied as one solution to overcome these solubility problems. Drug nanocrystals have comparatively simple structures which make them attractive for the formulation
[...] Read more.
Poor solubility of active pharmaceutical ingredients (APIs) is a great challenge for the pharmaceutical industry and, hence, drug nanocrystals are widely studied as one solution to overcome these solubility problems. Drug nanocrystals have comparatively simple structures which make them attractive for the formulation for poorly soluble drugs, and their capability to improve the dissolution in vitro is easily demonstrated, but turning the in vitro superior properties of nanocrystals to success in vivo, is often demanding: controlled (including enhanced) drug dissolution followed by successful permeation is not guaranteed, if for example, the dissolved drug precipitates before it is absorbed. In this review critical quality attributes related to nanocrystal formulations from production to final product performance in vivo are considered. Many important parameters exist, but here physical stability (aggregation tendency and solid state form), solubility properties influencing dissolution and supersaturation, excipient use to promote the maintenance of supersaturation, and finally the fate of nanocrystals in vivo are the main subjects of our focus. Full article
Open AccessArticle Role of Polymeric Excipients in the Stabilization of Olanzapine when Exposed to Aqueous Environments
Molecules 2015, 20(12), 22364-22382; doi:10.3390/molecules201219832
Received: 5 October 2015 / Revised: 25 November 2015 / Accepted: 2 December 2015 / Published: 12 December 2015
Cited by 1 | PDF Full-text (7011 KB) | HTML Full-text | XML Full-text
Abstract
Hydrate formation is a phase transition which can occur during manufacturing processes involving water. This work considers the prevention of hydration of anhydrous olanzapine and hydrate conversions in the presence of water and polymers (polyethyleneglycol; hydroxypropylcellulose; polyvinylpyrrolidone) in forming pellets by wet extrusion
[...] Read more.
Hydrate formation is a phase transition which can occur during manufacturing processes involving water. This work considers the prevention of hydration of anhydrous olanzapine and hydrate conversions in the presence of water and polymers (polyethyleneglycol; hydroxypropylcellulose; polyvinylpyrrolidone) in forming pellets by wet extrusion and spheronisation. Anhydrous olanzapine was added to water with or without those polymers prior to extrusion with microcrystalline cellulose. Assessment of olanzapine conversion was made by XRP-Diffraction; FTIR spectroscopy; calorimetry (DSC) and microscopy (SEM for crystal size and shape). The addition of water converted the anhydrous form into dihydrate B and higher hydrate; whereas polyethyleneglycol promoted a selective hydrate conversion into the higher hydrate olanzapine form. Both polyvinylpyrrolidone and hydroxypropylcellulose prevented the hydrate transformations of the anhydrous drug; the latter even in the presence of hydrate seeds. This may be explained by the higher H-bond ability; higher network association and higher hydrophobicity of hydroxypropylcellulose by comparison with polyethyleneglycol and polyvinylpyrrolidone; which could contribute to its higher affinity to the crystal surfaces of the hydrate nuclei/initial crystals and promoting steric hindrance to the incorporation of other drug molecules into the crystal lattice; thus, preventing the crystal growth. The addition of microcrystalline cellulose needed for the pellets production (final product) did not eliminate the protector effect of both hydroxypropylcellulose and polyvinylpyrrolidone during pellets’ processing and dissolution evaluation. Full article
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Open AccessReview Polymer-Based Prodrugs: Improving Tumor Targeting and the Solubility of Small Molecule Drugs in Cancer Therapy
Molecules 2015, 20(12), 21750-21769; doi:10.3390/molecules201219804
Received: 25 September 2015 / Revised: 5 November 2015 / Accepted: 17 November 2015 / Published: 4 December 2015
Cited by 10 | PDF Full-text (1505 KB) | HTML Full-text | XML Full-text
Abstract
The majority of anticancer drugs have poor aqueous solubility, produce adverse effects in healthy tissue, and thus impose major limitations on both clinical efficacy and therapeutic safety of cancer chemotherapy. To help circumvent problems associated with solubility, most cancer drugs are now formulated
[...] Read more.
The majority of anticancer drugs have poor aqueous solubility, produce adverse effects in healthy tissue, and thus impose major limitations on both clinical efficacy and therapeutic safety of cancer chemotherapy. To help circumvent problems associated with solubility, most cancer drugs are now formulated with co-solubilizers. However, these agents often also introduce severe side effects, thereby restricting effective treatment and patient quality of life. A promising approach to addressing problems in anticancer drug solubility and selectivity is their conjugation with polymeric carriers to form polymer-based prodrugs. These polymer-based prodrugs are macromolecular carriers, designed to increase the aqueous solubility of antitumor drugs, can enhance bioavailability. Additionally, polymer-based prodrugs approach exploits unique features of tumor physiology to passively facilitate intratumoral accumulation, and so improve chemodrug pharmacokinetics and pharmacological properties. This review introduces basic concepts of polymer-based prodrugs, provides an overview of currently emerging synthetic, natural, and genetically engineered polymers that now deliver anticancer drugs in preclinical or clinical trials, and highlights their major anticipated applications in anticancer therapies. Full article
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Open AccessArticle Characterization of Amorphous and Co-Amorphous Simvastatin Formulations Prepared by Spray Drying
Molecules 2015, 20(12), 21532-21548; doi:10.3390/molecules201219784
Received: 25 August 2015 / Revised: 24 November 2015 / Accepted: 25 November 2015 / Published: 3 December 2015
Cited by 2 | PDF Full-text (5780 KB) | HTML Full-text | XML Full-text
Abstract
In this study, spray drying from aqueous solutions, using the surface-active agent sodium lauryl sulfate (SLS) as a solubilizer, was explored as a production method for co-amorphous simvastatin–lysine (SVS-LYS) at 1:1 molar mixtures, which previously have been observed to form a co-amorphous mixture
[...] Read more.
In this study, spray drying from aqueous solutions, using the surface-active agent sodium lauryl sulfate (SLS) as a solubilizer, was explored as a production method for co-amorphous simvastatin–lysine (SVS-LYS) at 1:1 molar mixtures, which previously have been observed to form a co-amorphous mixture upon ball milling. In addition, a spray-dried formulation of SVS without LYS was prepared. Energy-dispersive X-ray spectroscopy (EDS) revealed that SLS coated the SVS and SVS-LYS particles upon spray drying. X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) showed that in the spray-dried formulations the remaining crystallinity originated from SLS only. The best dissolution properties and a “spring and parachute” effect were found for SVS spray-dried from a 5% SLS solution without LYS. Despite the presence of at least partially crystalline SLS in the mixtures, all the studied formulations were able to significantly extend the stability of amorphous SVS compared to previous co-amorphous formulations of SVS. The best stability (at least 12 months in dry conditions) was observed when SLS was spray-dried with SVS (and LYS). In conclusion, spray drying of SVS and LYS from aqueous surfactant solutions was able to produce formulations with improved physical stability for amorphous SVS. Full article
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Open AccessArticle Determination of Solubility Parameters of Ibuprofen and Ibuprofen Lysinate
Molecules 2015, 20(12), 21549-21568; doi:10.3390/molecules201219777
Received: 30 September 2015 / Revised: 23 October 2015 / Accepted: 28 October 2015 / Published: 3 December 2015
Cited by 6 | PDF Full-text (3430 KB) | HTML Full-text | XML Full-text
Abstract
In recent years there has been a growing interest in formulating solid dispersions, which purposes mainly include solubility enhancement, sustained drug release and taste masking. The most notable problem by these dispersions is drug-carrier (in)solubility. Here we focus on solubility parameters as a
[...] Read more.
In recent years there has been a growing interest in formulating solid dispersions, which purposes mainly include solubility enhancement, sustained drug release and taste masking. The most notable problem by these dispersions is drug-carrier (in)solubility. Here we focus on solubility parameters as a tool for predicting the solubility of a drug in certain carriers. Solubility parameters were determined in two different ways: solely by using calculation methods, and by experimental approaches. Six different calculation methods were applied in order to calculate the solubility parameters of the drug ibuprofen and several excipients. However, we were not able to do so in the case of ibuprofen lysinate, as calculation models for salts are still not defined. Therefore, the extended Hansen’s approach and inverse gas chromatography (IGC) were used for evaluating of solubility parameters for ibuprofen lysinate. The obtained values of the total solubility parameter did not differ much between the two methods: by the extended Hansen’s approach it was δt = 31.15 MPa0.5 and with IGC it was δt = 35.17 MPa0.5. However, the values of partial solubility parameters, i.e., δd, δp and δh, did differ from each other, what might be due to the complex behaviour of a salt in the presence of various solvents. Full article
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Open AccessArticle Improved Antioxidant Capacity of Optimization of a Self-Microemulsifying Drug Delivery System for Resveratrol
Molecules 2015, 20(12), 21167-21177; doi:10.3390/molecules201219750
Received: 16 September 2015 / Revised: 13 November 2015 / Accepted: 17 November 2015 / Published: 27 November 2015
Cited by 1 | PDF Full-text (6183 KB) | HTML Full-text | XML Full-text
Abstract
The use of nano-encapsulated resveratrol (RSV) in self-micro-emulsified drug delivery systems (SMEDDS) formulations was investigated. Self-emulsifying grading tests were used to establish the optimal ratio of oil, surfactant, and co-surfactant. The optimized system was further investigated for the droplet size and zeta potential
[...] Read more.
The use of nano-encapsulated resveratrol (RSV) in self-micro-emulsified drug delivery systems (SMEDDS) formulations was investigated. Self-emulsifying grading tests were used to establish the optimal ratio of oil, surfactant, and co-surfactant. The optimized system was further investigated for the droplet size and zeta potential at the different medium pH values by a Malvern Zetasizer and transmission electron microscopy (TEM). The antioxidant capacity and cytotoxicity of the formulation were detected by DCFH-DA and a CCK-8 assays. The results showed that the nano-emulsion based on ethyl oleate, Tween-80, and PEG-400 (35:40:25, w/w/w) was the most stable formulation due to the small droplet size (approximately 50 nm) and high zeta potential in a neutral environment. Furthermore, this formulation also exhibited a greater antioxidant capacity with less toxicity than free RSV. Taken together, considering these results and the simple fabrication process, this formulation could be used to deliver nutritional food supplements in a stable, efficient, and safe manner. Full article
Open AccessArticle Development and Evaluation of Liquid and Solid Self-Emulsifying Drug Delivery Systems for Atorvastatin
Molecules 2015, 20(12), 21010-21022; doi:10.3390/molecules201219745
Received: 27 August 2015 / Revised: 17 October 2015 / Accepted: 20 November 2015 / Published: 25 November 2015
Cited by 3 | PDF Full-text (3279 KB) | HTML Full-text | XML Full-text
Abstract
The objective of this work was to design and characterize liquid and solid self-emulsifying drug delivery systems (SEDDS) for poorly soluble atorvastatin. To optimize the composition of liquid atorvastatin-SEDDS, solubility tests, pseudoternary phase diagrams, emulsification studies and other in vitro examinations (thermodynamic stability,
[...] Read more.
The objective of this work was to design and characterize liquid and solid self-emulsifying drug delivery systems (SEDDS) for poorly soluble atorvastatin. To optimize the composition of liquid atorvastatin-SEDDS, solubility tests, pseudoternary phase diagrams, emulsification studies and other in vitro examinations (thermodynamic stability, droplet size and zeta potential analysis) were performed. Due to the disadvantages of liquid SEDDS (few choices for dosage forms, low stability and portability during the manufacturing process), attempts were also made to obtain solid SEDDS. Solid SEDDS were successfully obtained using the spray drying technique from two optimized liquid formulations, CF3 and OF2. Despite liquid SEDDS formulation, CF3 was characterized by lower turbidity, higher percentage transmittance and better self-emulsifying properties, and based on the in vitro dissolution study it can be concluded that better solubilization properties were exhibited by solid formulation OF2. Overall, the studies demonstrated the possibility of formulating liquid and solid SEEDS as promising carriers of atorvastatin. SEDDS, with their unique solubilization properties, provide the opportunity to deliver lipophilic drugs to the gastrointestinal tract in a solubilized state, avoiding dissolution—a restricting factor in absorption rate of BCS Class 2 drugs, including atorvastatin. Full article
Open AccessReview Hydrogel-Based Drug Delivery Systems for Poorly Water-Soluble Drugs
Molecules 2015, 20(11), 20397-20408; doi:10.3390/molecules201119705
Received: 13 October 2015 / Revised: 2 November 2015 / Accepted: 6 November 2015 / Published: 13 November 2015
Cited by 7 | PDF Full-text (771 KB) | HTML Full-text | XML Full-text
Abstract
Hydrogels are three-dimensional materials that can withstand a great amount of water incorporation while maintaining integrity. This allows hydrogels to be very unique biomedical materials, especially for drug delivery. Much effort has been made to incorporate hydrophilic molecules in hydrogels in the field
[...] Read more.
Hydrogels are three-dimensional materials that can withstand a great amount of water incorporation while maintaining integrity. This allows hydrogels to be very unique biomedical materials, especially for drug delivery. Much effort has been made to incorporate hydrophilic molecules in hydrogels in the field of drug delivery, while loading of hydrophobic drugs has not been vastly studied. However, in recent years, research has also been conducted on incorporating hydrophobic molecules within hydrogel matrices for achieving a steady release of drugs to treat various ailments. Here, we summarize the types of hydrogels used as drug delivery vehicles, various methods to incorporate hydrophobic molecules in hydrogel matrices, and the potential therapeutic applications of hydrogels in cancer. Full article
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Open AccessArticle Multivariate Quantification of the Solid State Phase Composition of Co-Amorphous Naproxen-Indomethacin
Molecules 2015, 20(10), 19571-19587; doi:10.3390/molecules201019571
Received: 25 September 2015 / Revised: 19 October 2015 / Accepted: 21 October 2015 / Published: 27 October 2015
Cited by 3 | PDF Full-text (2280 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
To benefit from the optimized dissolution properties of active pharmaceutical ingredients in their amorphous forms, co-amorphisation as a viable tool to stabilize these amorphous phases is of both academic and industrial interest. Reports dealing with the physical stability and recrystallization behavior of co-amorphous
[...] Read more.
To benefit from the optimized dissolution properties of active pharmaceutical ingredients in their amorphous forms, co-amorphisation as a viable tool to stabilize these amorphous phases is of both academic and industrial interest. Reports dealing with the physical stability and recrystallization behavior of co-amorphous systems are however limited to qualitative evaluations based on the corresponding X-ray powder diffractograms. Therefore, the objective of the study was to develop a quantification model based on X-ray powder diffractometry (XRPD), followed by a multivariate partial least squares regression approach that enables the simultaneous determination of up to four solid state fractions: crystalline naproxen, γ-indomethacin, α-indomethacin as well as co-amorphous naproxen-indomethacin. For this purpose, a calibration set that covers the whole range of possible combinations of the four components was prepared and analyzed by XRPD. In order to test the model performances, leave-one-out cross validation was performed and revealed root mean square errors of validation between 3.11% and 3.45% for the crystalline molar fractions and 5.57% for the co-amorphous molar fraction. In summary, even four solid state phases, involving one co-amorphous phase, can be quantified with this XRPD data-based approach. Full article
Open AccessReview Polymorph Impact on the Bioavailability and Stability of Poorly Soluble Drugs
Molecules 2015, 20(10), 18759-18776; doi:10.3390/molecules201018759
Received: 11 September 2015 / Revised: 6 October 2015 / Accepted: 8 October 2015 / Published: 15 October 2015
Cited by 12 | PDF Full-text (796 KB) | HTML Full-text | XML Full-text
Abstract
Drugs with low water solubility are predisposed to poor and variable oral bioavailability and, therefore, to variability in clinical response, that might be overcome through an appropriate formulation of the drug. Polymorphs (anhydrous and solvate/hydrate forms) may resolve these bioavailability problems, but they
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Drugs with low water solubility are predisposed to poor and variable oral bioavailability and, therefore, to variability in clinical response, that might be overcome through an appropriate formulation of the drug. Polymorphs (anhydrous and solvate/hydrate forms) may resolve these bioavailability problems, but they can be a challenge to ensure physicochemical stability for the entire shelf life of the drug product. Since clinical failures of polymorph drugs have not been uncommon, and some of them have been entirely unexpected, the Food and Drug Administration (FDA) and the International Conference on Harmonization (ICH) has required preliminary and exhaustive screening studies to identify and characterize all the polymorph crystal forms for each drug. In the past, the polymorphism of many drugs was detected fortuitously or through manual time consuming methods; today, drug crystal engineering, in particular, combinatorial chemistry and high-throughput screening, makes it possible to easily and exhaustively identify stable polymorphic and/or hydrate/dehydrate forms of poorly soluble drugs, in order to overcome bioavailability related problems or clinical failures. This review describes the concepts involved, provides examples of drugs characterized by poor solubility for which polymorphism has proven important, outlines the state-of-the-art technologies and discusses the pertinent regulations. Full article
Open AccessArticle Highly Stable Tetra-Phenolato Titanium(IV) Agent Formulated into Nanoparticles Demonstrates Anti-Tumoral Activity and Selectivity
Molecules 2015, 20(10), 18526-18538; doi:10.3390/molecules201018526
Received: 1 September 2015 / Revised: 30 September 2015 / Accepted: 5 October 2015 / Published: 9 October 2015
Cited by 4 | PDF Full-text (847 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Titanium(IV) complexes exhibit high potential as anti-tumor agents, particularly due to their low intrinsic toxicity and cytotoxicity toward cisplatin resistant cells. Nevertheless, Ti(IV) complexes generally undergo rapid hydrolysis that previously hampered their utilization as anticancer drugs. We recently overcame this difficulty by developing
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Titanium(IV) complexes exhibit high potential as anti-tumor agents, particularly due to their low intrinsic toxicity and cytotoxicity toward cisplatin resistant cells. Nevertheless, Ti(IV) complexes generally undergo rapid hydrolysis that previously hampered their utilization as anticancer drugs. We recently overcame this difficulty by developing a highly stable Ti(IV) complex that is based on tetra-phenolato, hexadentate ligand, formulated into organic nanoparticles. Herein we investigated the activity of this complex in vitro and in vivo. Although inactive when tested directly due to poor solubility, when formulated, this complex displayed (a) high cytotoxicity toward cisplatin resistant human ovarian cells, A2780-cp, with resistance factor of 1.1; (b) additive behavior in combination with cisplatin toward ovarian and colon cancer cells; (c) selectivity toward cancer cells as implied by its mild activity toward non-cancerous, fibroblast lung cells, MRC-5; (d) high stability and durability as manifested by the ability to maintain cytotoxicity, even following one week of incubation in 100% aquatic medium solution; and (e) in vivo efficacy toward solid tumors of human colon cancer cells, HT-29, in nude mice without any clinical signs of toxicity. These features support the formulated phenolato Ti(IV) complex being an effective and selective anti-tumoral agent. Full article
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Open AccessArticle Investigating the Dissolution Performance of Amorphous Solid Dispersions Using Magnetic Resonance Imaging and Proton NMR
Molecules 2015, 20(9), 16404-16418; doi:10.3390/molecules200916404
Received: 9 July 2015 / Revised: 30 August 2015 / Accepted: 2 September 2015 / Published: 10 September 2015
Cited by 5 | PDF Full-text (2273 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
We have investigated the dissolution performance of amorphous solid dispersions of poorly water-soluble bicalutamide in a Kollidon VA64 polymeric matrix as a function of the drug loading (5% vs. 30% bicalutamide). A combined suite of state-of-the-art analytical techniques were employed to obtain a
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We have investigated the dissolution performance of amorphous solid dispersions of poorly water-soluble bicalutamide in a Kollidon VA64 polymeric matrix as a function of the drug loading (5% vs. 30% bicalutamide). A combined suite of state-of-the-art analytical techniques were employed to obtain a clear picture of the drug release, including an integrated magnetic resonance imaging UV-Vis flow cell system and 1H-NMR. Off-line 1H-NMR was used for the first time to simultaneously measure the dissolution profiles and rates of both the drug and the polymer from a solid dispersion. MRI and 1H-NMR data showed that the 5% drug loading compact erodes linearly, and that bicalutamide and Kollidon VA64 are released at approximately the same rate from the molecular dispersion. For the 30% extrudate, data indicated a slower water ingress into the compact which corresponds to a slower dissolution rate of both bicalutamide and Kollidon VA64. Full article
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Open AccessArticle Characterization of the Sublimation and Vapor Pressure of 2-(2-Nitrovinyl) Furan (G-0) Using Thermogravimetric Analysis: Effects of Complexation with Cyclodextrins
Molecules 2015, 20(8), 15175-15191; doi:10.3390/molecules200815175
Received: 3 July 2015 / Revised: 15 August 2015 / Accepted: 17 August 2015 / Published: 19 August 2015
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Abstract
In the present work, the sublimation of crystalline solid 2-(2-nitrovinyl) furan (G-0) in the temperature range of 35 to 60 °C (below the melting point of the drug) was studied using thermogravimetric analysis (TGA). The sublimated product was characterized using Fourier-transformed-infrared spectroscopy (FT-IR)
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In the present work, the sublimation of crystalline solid 2-(2-nitrovinyl) furan (G-0) in the temperature range of 35 to 60 °C (below the melting point of the drug) was studied using thermogravimetric analysis (TGA). The sublimated product was characterized using Fourier-transformed-infrared spectroscopy (FT-IR) and thin layer chromatography (TLC). The sublimation rate at each temperature was obtained using the slope of the linear regression model and followed apparent zero-order kinetics. The sublimation enthalpy from 35 to 60 °C was obtained from the Eyring equation. The Gückel method was used to estimate the sublimation rate and vapor pressure at 25 °C. Physical mixtures, kneaded and freeze-dried complexes were prepared with 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and sulfobutyl ether-β-cyclodextrin (SBE-β-CD) and analyzed using isothermal TGA at 50 °C. The complexation contributed to reducing the sublimation process. The best results were achieved using freeze-dried complexes with both cyclodextrins. Full article
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Open AccessArticle Influence of Solid Drug Delivery System Formulation on Poorly Water-Soluble Drug Dissolution and Permeability
Molecules 2015, 20(8), 14684-14698; doi:10.3390/molecules200814684
Received: 9 June 2015 / Revised: 26 July 2015 / Accepted: 5 August 2015 / Published: 13 August 2015
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Abstract
The majority of drugs have a low dissolution rate, which is a limiting step for their absorption. In this manuscript, solid dispersions (SD), solid self-microemulsifying drug delivery systems (S-SMEDDS) and solid self-nanoemulsifying drug delivery systems (S-SNEDDS) were evaluated as potential formulation strategies to
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The majority of drugs have a low dissolution rate, which is a limiting step for their absorption. In this manuscript, solid dispersions (SD), solid self-microemulsifying drug delivery systems (S-SMEDDS) and solid self-nanoemulsifying drug delivery systems (S-SNEDDS) were evaluated as potential formulation strategies to increase the dissolution rate of carbamazepine. Influence of increased dissolution rate on permeability of carbamazepine was evaluated using PAMPA test. In S-SMEDDS and S-SNEDDS formulations, the ratio of liquid SMEDDS/SNEDDS and solid carrier (Neusilin® UFL2) was varied, and carbamazepine content was constant. In SD formulations, the ratio of carbamazepine and Neusilin® UFL2, was varied. Formulations that showed the best dissolution rate of carbamazepine (SD_1:6, SMEDDS_1:1, SNEDDS_1:6) were mutually compared, characterization of these formulations was performed by DSC, PXRD and FT-IR analyses, and a PAMPA test was done. All formulations have shown a significant increase in dissolution rate compared to pure carbamazepine and immediate-release carbamazepine tablets. Formulation S-SMEDDS_1:1 showed the fastest release rate and permeability of carbamazepine. DSC, PXRD and FT-IR analyses confirmed that in S-SMEDDS and S-SNEDDS carbamazepine remained in polymorph form III, and that it was converted to an amorphous state in SD formulations. All formulations showed increased permeability of carbamazepine, compared to pure carbamazepine. Full article
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Open AccessArticle The Enhanced Inhibitory Effect of Different Antitumor Agents in Self-Microemulsifying Drug Delivery Systems on Human Cervical Cancer HeLa Cells
Molecules 2015, 20(7), 13226-13239; doi:10.3390/molecules200713226
Received: 5 May 2015 / Revised: 6 July 2015 / Accepted: 7 July 2015 / Published: 21 July 2015
Cited by 5 | PDF Full-text (999 KB) | HTML Full-text | XML Full-text
Abstract
The aim of this study was to develop topical self-microemulsifying drug delivery systems (SMEDDS) containing antitumor agents (bleomycin, cisplatin and ifosfamide) and to investigate their inhibitory potential in SMEDDS on human cervical cancer HeLa cells. The physicochemical properties of cytostatic drug loaded SMEDDS
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The aim of this study was to develop topical self-microemulsifying drug delivery systems (SMEDDS) containing antitumor agents (bleomycin, cisplatin and ifosfamide) and to investigate their inhibitory potential in SMEDDS on human cervical cancer HeLa cells. The physicochemical properties of cytostatic drug loaded SMEDDS were characterized. The cytotoxicity of main components of SMEDDS was also investigated. Their IC50 values were determined. HeLa cells were treated by different concentrations of cisplatin, bleomycin and ifosfamide alone and in various SMEDDS. The inhibitory effect on cell growth was analyzed by MTT cell viability assay. Inflammation is a driving force that accelerates cancer development. The inhibitory effect of these antitumor agents has also been tested on HeLa cells in the presence of inflammatory mediators (IL-1-β, TNF-α) as an in vitro model of inflamed human cervix. Significant differences in the cytotoxicity of cytostatic drugs alone and in SMEDDS have been found in a concentration-dependent manner. The self-micro emulsifying system may potentiate the effectiveness of bleomycin, cisplatin and ifosfamide topically. The effect of SMEDDS containing antitumor agents was decreased significantly in the presence of inflammatory mediators. According to our experiments, the optimal SMEDDS formulation is 1:1:2:6:2 ratios of Isopropyl myristate, Capryol 90, Kolliphor RH 40, Cremophor RH40, Transcutol HP and Labrasol. It can be concluded that SMEDDS may increase the inhibitory effect of bleomycin, ifosfamide and cisplatin on human cervical cancer HeLa cells. Inflammation on HeLa cells hinders the effectiveness of SMEDDS containing antitumor agents. Our results might ensure useful data for development of optimal antitumor formulations. Full article
Open AccessArticle Characterization and Pharmacokinetic Study of Aprepitant Solid Dispersions with Soluplus®
Molecules 2015, 20(6), 11345-11356; doi:10.3390/molecules200611345
Received: 27 April 2015 / Revised: 28 May 2015 / Accepted: 1 June 2015 / Published: 19 June 2015
Cited by 6 | PDF Full-text (2236 KB) | HTML Full-text | XML Full-text
Abstract
Solid dispersions are a useful approach to improve the dissolution rate and bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs). The aim of this study was to improve the physicochemical properties and bioavailability of a poorly water-soluble aprepitant by preparation of solid dispersions.
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Solid dispersions are a useful approach to improve the dissolution rate and bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs). The aim of this study was to improve the physicochemical properties and bioavailability of a poorly water-soluble aprepitant by preparation of solid dispersions. The solid dispersions were characterized by dissolution, FTIR, XRPD, DSC, SEM and pharmacokinetic studies in rats. The dissolution rate of the aprepitant was significantly increased by solid dispersions, and XRD, DSC, and SEM analysis indicated that the aprepitant existed in an amorphous form within the solid dispersions. The result of dissolution study showed that the dissolution rate of SDs was nearly five-fold faster than aprepitant. FTIR spectrometry suggested the presence of intermolecular hydrogen bonds between the aprepitant and polymer. Pharmacokinetic studies in rats indicated that the degree drug absorption was comparable with that of Emend®. Aprepitant exists in an amorphous state in solid dispersions and the solid dispersions can markedly improve the dissolution and oral bioavailability of the aprepitant. The AUC0–t of the SDs was 2.4-fold that of the aprepitant. In addition, the method and its associated techniques are very easy to carry out. Full article
Open AccessArticle Enhanced Supersaturation and Oral Absorption of Sirolimus Using an Amorphous Solid Dispersion Based on Eudragit® E
Molecules 2015, 20(6), 9496-9509; doi:10.3390/molecules20069496
Received: 10 April 2015 / Accepted: 20 May 2015 / Published: 25 May 2015
Cited by 5 | PDF Full-text (2647 KB) | HTML Full-text | XML Full-text
Abstract
The present study aimed to investigate the effect of Eudragit® E/HCl (E-SD) on the degradation of sirolimus in simulated gastric fluid (pH 1.2) and to develop a new oral formulation of sirolimus using E-SD solid dispersions to enhance oral bioavailability. Sirolimus-loaded solid
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The present study aimed to investigate the effect of Eudragit® E/HCl (E-SD) on the degradation of sirolimus in simulated gastric fluid (pH 1.2) and to develop a new oral formulation of sirolimus using E-SD solid dispersions to enhance oral bioavailability. Sirolimus-loaded solid dispersions were fabricated by a spray drying process. A kinetic solubility test demonstrated that the sirolimus/E-SD/TPGS (1/8/1) solid dispersion had a maximum solubility of 196.7 μg/mL within 0.5 h that gradually decreased to 173.4 μg/mL after 12 h. According to the dissolution study, the most suitable formulation was the sirolimus/E-SD/TPGS (1/8/1) solid dispersion in simulated gastric fluid (pH 1.2), owing to enhanced stability and degree of supersaturation of E-SD and TPGS. Furthermore, pharmacokinetic studies in rats indicated that compared to the physical mixture and sirolimus/HPMC/TPGS (1/8/1) solid dispersion, the sirolimus/E-SD/TPGS (1/8/1) solid dispersion significantly improved oral absorption of sirolimus. E-SD significantly inhibited the degradation of sirolimus in a dose-dependent manner. E-SD also significantly inhibited the precipitation of sirolimus compared to hydroxypropylmethyl cellulose (HPMC). Therefore, the results from the present study suggest that the sirolimus-loaded E-SD/TPGS solid dispersion has great potential in clinical applications. Full article

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