Quantifying solubility enhancement due to particle size reduction and crystal habit modification: case study of acetyl salicylic acid

The poor solubility of potential drug molecules is a significant problem in the design of pharmaceutical formulations. It is well known, however, that the solubility of crystalline materials is enhanced when the particle size is reduced to submicron levels and this factor can be expected to enhance drug product bioavailability. Direct estimation of solubility enhancement, as calculated via the Gibbs-Thompson relationship, demands reasonably accurate values for the particle/solution interfacial tension and, in particular, its anisotropy with respect to the crystal product's habit and morphology. In this article, an improved, more molecule-centered, approach is presented towards the calculation of solubility enhancement factors in which molecular modeling techniques are applied, and the effects associated with both crystal habit modification and solvent choice are examined. A case study for facetted, acetyl salicylic acid (aspirin) crystals in equilibrium with saturated aqueous ethanol solution reveals that their solubility will be enhanced in the range (7-58%) for a crystal size of 0.02 microm, with significantly higher enhancement for crystal morphologies in which the hydrophobic crystal faces are more predominant than the hydrophilic faces and for solvents in which the solubility is smaller.     

Mixed hydrotropy: novel science of solubility enhancement

Conventional furosemide tablets are practically insoluble in water, have slow onset of action (45-60 min) and poor bioavailability (39-53%), and therefore cannot be given in emergency clinical situations like hypertension or pulmonary edema. So purpose of research was to provide a fast dissolving oral dosage form of furosemide, which can provide quick onset of action by using concept of mixed hydrotropy. Initially solubility of furosemide was determined individually in 4 hydrotropic agents namely urea, sodium acetate, sodium benzoate, sodium citrate at concentration of 10, 20, 30 and 40% w/v solutions using purified water as solvent. Highest solubility was obtained in 40% sodium benzoate solution. Then different combinations of 2, 3 and 4 hydrotropic agents in different ratios were used to determine solubility, so that total concentration of hydrotropic agents was always 40%. Highest solubility was obtained in solution of urea+sodium benzoate+sodium citrate at optimum ratio of 15:20:5. This optimized combination was utilized in preparing solid dispersions by common solvent technique using distilled water as solvent. Solid dispersions were evaluated for flow properties, XRD, DSC, SEM and were also compressed to form tablets. Dissolution studies of conventional and prepared tablets were done using USP Type II apparatus. It was concluded that the concept of mixed hydrotropic solid dispersion is novel, safe and cost-effective technique for enhancing bioavailability of poorly water-soluble drugs by dissolving drug in nonionized form. The magical enhancement in solubility of furosemide is clear indication of its potential to be used in future for other poorly water-soluble drugs in which low bioavailability is major concern.     

Liposome formulation of paclitaxel with enhanced solubility and stability

Despite its strong antitumor activity, paclitaxel (Taxol®) has limited clinical applications due to its low aqueous solubility and hypersensitivity caused by Cremophor® EL and ethanol which is the vehicle used in the current commercial product. In an attempt to develop a pharmaceutically acceptable formulation that could replace Taxol®, a paclitaxel incorporated liposome has been constructed to improve solubility and physicochemical stability. The effect of various components of the liposome, including cholesterol and lipid, on the solubility and entrapment efficiency (EE) of paclitaxel was systematically investigated. The results showed that 5% (v/v) of polyethylene glycol 400 in the hydration medium of liposome significantly increased the solubility (up to 3.39 mg/mL) as well as the EE and the paclitaxel content in the liposome formulation composed of 10% (w/v) of S₁₀₀PC with cholesterol (cholesterol-to-lipid molar ratio = 10:90). When sucrose (sugar-to-lipid molar ratio = 2.3) was added as a lyoprotectant during the freeze-drying of the liposome, physicochemical stability of liposome was significantly improved. Moreover, the cytotoxicity of the final liposome formulation against MDA-MB-231 human breast cancer cell line was not significantly different from that of Taxol®. The enhanced aqueous solubility as well as the physicochemical stability of paclitaxel in the liposome formulation developed in this study could be a safer and effective alternative to the Cremophor® EL and ethanol formulation.     

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.     

Design,formulation and evaluation of Azithromycin binary solid dispersions using Kolliphor series for the solubility and in vitro dissolution rate enhancement

The main purpose of this investigation is increasing of the solubility and dissolution rate of Azithromycin by solid dispersion technique using Kolliphor P 237, Kolliphor P 338 and Kolliphor P 407. Kolliphor (P 237, P 338 and P 407) in various properties by weight {(1:0.5), (1:1), (1:1.5) and (1:2)}, utilizing solvent evaporation method. Dissolution studies carried out in phosphate buffer with pH 6.0 according to US pharmacopoeia method. The drug release profiles were studied, so we found that the dissolution rate of the drug (by calculating the dissolution parameters) was significantly increase compared to pure drug, also solubility of physical mixtures as well as solid dispersions increased compared to the intact drug. For example solubility of the drug increased from 85–753 μg mL^?1 (for Kolliphor P 237; 8 times more). The best results were as follows: Kolliphor P 237 > Kolliphor P 338 > Kolliphor P 407. IR spectra revealed no chemical incompatibility between drug and polymer. Drug-polymer interactions were investigated using differential scanning calorimetry, powder X-ray diffraction and scanning election microscopy. The dissolution rate and solubility of Azithromycin solid dispersions was improved significantly using Kolliphor. In addition, the simplicity of this method is very effective and have been met the project objectives.     

Microemulsion based vaginal gel of fluconazole: formulation, in vitro and in vivo evaluation

The objective of the present investigation was to develop and evaluate microemulsion based gel for the vaginal delivery of fluconazole (FLZ). The solubility of FLZ in oils and surfactants was evaluated to identify components of the microemulsion. The ternary diagram was plotted to identify the area of microemulsion existence. Various gelling agents were evaluated for their potential to gel the FLZ microemulsion without affecting its structure. The bioadhesive potential and anti-fungal activity of the FLZ microemulsion based gel (FLZ-MBG) was determined in comparison to the marketed clotrimazole gel (Candid V gel) by in vitro methods. The vaginal irritation potential of the FLZ-MBG was evaluated in rabbits. The clinical efficacy of the FLZ-MBG and Candid V gel was evaluated in females suffering from vaginal candidiasis. The FLZ microemulsion exhibited globule size of 24 nm and polydispersity index of 0.98. Carbopol ETD 2020 could successfully gel the FLZ microemulsion without disturbing the structure. The FLZ-MBG showed significantly higher (P<0.05) in vitro bioadhesion and anti-fungal activity as compared to that of Candid V gel. The FLZ-MBG did not show any signs of vaginal irritation in the rabbits. The small-scale clinical studies indicated that the FLZ-MBG shows faster onset of action than Candid V gel although no difference was observed in the clinical efficacy.     

Bioavailability enhancement strategies: basics, formulation approaches and regulatory considerations

Poor solubility remains a major challenge for pharmaceutical industry, which is now considered to be an area of prime importance in the field of biomedical research. Approximately 40% new molecular entities (NMEs) synthesized in pharmaceutical R with advanced combinatorial chemistry and computer aided drug designing (CADD) approaches suffer from poor solubility and bioavailability related issues. Apart from these presence of intestinal tight junctional epithelial cells, transporters and enzymatic barriers further reduces the oral absorption of drugs. Implication of the novel lipid based nanocarriers and nanomaterials like dendrimers and carbon nanotubes as a delivery system can effectively enhance the oral bioavailability of drugs by breaching the barriers, and resolve all critics related to solubility and bioavailability. Thus prime objectives of this review are to give in-depth knowledge and critical appraisal on the barriers for poor oral bioavailability of drugs, along with various novel formulation approaches used for bioavailability enhancement such as lipid based formulations, nanosizing techniques, complexation with polymers and nanomaterials like dendrimers, carbon nanotubes, and penetration enhancers. Also it gives a brief account on in vitro, in vivo screening methods used for assessment of oral bioavailability, and regulatory considerations for the approval.     

Caffeine: A potential complexing agent for solubility and dissolution enhancement of celecoxib

Complexation of caffeine with the drug celecoxib was used to enhance its solubility as well as in vitro dissolution in the present investigation. Caffeine was extracted from tea leaves using the sublimation method. A molecular complex (1:1) of caffeine–celecoxib was prepared using the solubility method. The solubility of celecoxib in distilled water and the caffeine complex was determined using a HPLC method at a wavelength of 250?nm. Dissolution studies of pure celecoxib, a marketed capsule (Celebrex^®), and the complex were performed using USP dissolution apparatus I for pure celecoxib and the complex and apparatus II for the capsule in distilled water. The highest solubility (48.32?mg/mL) as well as percent dissolution (90.54%) of celecoxib was obtained with the caffeine–celecoxib complex. The results for solubility and dissolution were highly significant as compared to pure celecoxib and the marketed capsule (p?<?0.01). These results suggest that caffeine is a promising complexing agent for solubility as well as dissolution enhancement of the poorly soluble drug celecoxib.     

Pharmacological enhancement of fear reduction: preclinical models

Anxiety disorders have a high prevalence, and despite the substantial advances in the psychological treatment of anxiety, relapse is still a common problem. One approach to improving existing psychological treatments for anxiety has been to develop pharmacological agents that can be used to enhance the processes underlying exposure therapy, which is the most commonly used and empirically validated psychological treatment for anxiety during which individuals are taught to appropriately inhibit fear. Animal models of exposure therapy, particularly fear extinction, have proved to be a very useful way of examining the neural and molecular correlates of fear inhibition, which has in turn led to the identification of numerous drugs that enhance these processes in rats. Several of these drugs have subsequently been tested as novel pharmacological adjuncts to exposure therapy in humans with a range of anxiety disorders. The purpose of this review is to outline the key animal models of exposure therapy and to describe how these have been used to develop potential pharmacological adjuncts for anxiety disorders. Drugs that are currently in clinical use, as well as those currently in the preclinical stages of investigation, are described.     

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.     

Oral formulation strategies to improve solubility of poorly water-soluble drugs

INTRODUCTION: In the past two decades, there has been a spiraling increase in the complexity and specificity of drug-receptor targets. It is possible to design drugs for these diverse targets with advances in combinatorial chemistry and high throughput screening. Unfortunately, but not entirely unexpectedly, these advances have been accompanied by an increase in the structural complexity and a decrease in the solubility of the active pharmaceutical ingredient. Therefore, the importance of formulation strategies to improve the solubility of poorly water-soluble drugs is inevitable, thus making it crucial to understand and explore the recent trends. AREAS COVERED: Drug delivery systems (DDS), such as solid dispersions, soluble complexes, self-emulsifying drug delivery systems (SEDDS), nanocrystals and mesoporous inorganic carriers, are discussed briefly in this review, along with examples of marketed products. This article provides the reader with a concise overview of currently relevant formulation strategies and proposes anticipated future trends. EXPERT OPINION: Today, the pharmaceutical industry has at its disposal a series of reliable and scalable formulation strategies for poorly soluble drugs. However, due to a lack of understanding of the basic physical chemistry behind these strategies, formulation development is still driven by trial and error.     

Oral formulation strategies to improve solubility of poorly water-soluble drugs

Introduction: In the past two decades, there has been a spiraling increase in the complexity and specificity of drug–receptor targets. It is possible to design drugs for these diverse targets with advances in combinatorial chemistry and high throughput screening. Unfortunately, but not entirely unexpectedly, these advances have been accompanied by an increase in the structural complexity and a decrease in the solubility of the active pharmaceutical ingredient. Therefore, the importance of formulation strategies to improve the solubility of poorly water-soluble drugs is inevitable, thus making it crucial to understand and explore the recent trends.

Areas covered: Drug delivery systems (DDS), such as solid dispersions, soluble complexes, self-emulsifying drug delivery systems (SEDDS), nanocrystals and mesoporous inorganic carriers, are discussed briefly in this review, along with examples of marketed products. This article provides the reader with a concise overview of currently relevant formulation strategies and proposes anticipated future trends.

Expert opinion: Today, the pharmaceutical industry has at its disposal a series of reliable and scalable formulation strategies for poorly soluble drugs. However, due to a lack of understanding of the basic physical chemistry behind these strategies, formulation development is still driven by trial and error.     

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.     

Enhancement of solubility and dissolution of Coenzyme Q10 using solid dispersion formulation

This study aimed to develop a stable solid dispersion of Coenzyme Q₁₀ (CoQ₁₀) with high aqueous solubility and dissolution rate. Among various carriers screened, poloxamer 407 was most effective to form a superior solid dispersion of CoQ₁₀ having significantly enhanced solubility. Particularly, solid dispersion of CoQ₁₀ with poloxamer 407 in the weight ratio of 1:5 prepared by melting method enhanced the solubility of CoQ₁₀ to the greatest extent. However, it exhibited poor stability and hence Aerosil^® 200 (colloidal silicon dioxide) was incorporated into the solid dispersion as an adsorbent to inhibit the recrystallization process. The solid dispersion of CoQ₁₀, poloxamer 407 and Aerosil^® 200 in the weight ratio of 1:5:6 exhibited improved stability with no significant change in solubility during the 1-month stability test. Moreover, the solid dispersion formulation containing Aerosil^® 200 significantly enhanced the extent of drug release (approx. 75% release) as well as the dissolution rate of CoQ₁₀. In conclusion, the present study has developed the stable solid dispersion formulation of CoQ₁₀ with poloxamer 407 and Aerosil^® 200 for the enhanced solubility and dissolution of CoQ₁₀, which could also offer some additional advantages including ease of preparation, good flowability and cost-effectiveness.     

Application of dendrimer-drug complexation in the enhancement of drug solubility and bioavailability

Dendrimers are 3D, hyperbranched, tree-like polymers having immense potential in drug delivery, targeting, diagnosis and as carriers for DNA/gene delivery. Dendrimers have hydrophilic exteriors and hydrophilic interiors, which are responsible for its unimolecular micellar nature. They form covalent as well as non-covalent complexes with drug molecules and hydrophobes, which are responsible for its solubilisation behaviour. Dendrimer mediated complexation is advantageous in terms of stability, controlled release, high drug payload and reduced toxicity of entrapped drug(s). Studies on non-covalent interaction of dendrimers with drugs are in abundance so far as solubilisation is concerned. However, the non-covalent complexation often leads to lower drug encapsulation and complex stability compared to covalent conjugation. High drug payload and stability leads to higher bioavailability of the drugs. In addition dendrimers can be surface engineered to release the drug at desired site, that is, as targeted drug delivery. This property along with the solubilisation behaviour could improve the bioavailability of drugs.     

Preparation and solid-state characterization of ball milled saquinavir mesylate for solubility enhancement

Saquinavir is an anti-retroviral drug with very low oral bioavailability (e.g. 0.7-4.0%) due to its affinity toward efflux transporters (P-gp) and metabolic enzymes (CYP3A4). The aim of this study was to characterize the effects of high-energy ball milling on saquinavir solid-state characteristics and aqueous solubility for the design of effective buccal drug delivery systems. The solubility of saquinavir mesylate was evaluated in simulated saliva before and after milling for 1, 3, 15, 30, 50, and 60 h. To elucidate changes in crystallinity and long-range structure in the drug, analyses of the milled powders were performed using XRD, ATR-IR, DSC/TGA, BET surface area, EDX and SEM. In addition, the effects of milling time on saquinavir solubility were statistically correlated using repeated measures ANOVA. Results of this study indicate that the milling of saquinavir mesylate produces nanoporous particles with unique surface structures, thermal properties, and increased aqueous solubility. Optimal milling time occurred at 3 h and corresponded to a 9-fold solubility enhancement in simulated saliva. Thermal analysis revealed only a slight decrease in melting point (T_m) from 242 °C to 236 °C after 60 h milling. XRD diffractograms indicate a gradual crystalline-to-amorphous transition with some residual crystallinity remaining after 60 h milling time. Unstable polymorphic structures appeared between 15 and 30 h which were converted to more stable isomorphs at 60 h. Aggregate formation also seems to occur after 15 h but no metal contamination of the drug was observed during the milling process as determined by EDX analysis. In conclusion, high-energy ball milling may be a method of choice for improving the solubility of saquinavir and facilitating novel drug formulations design.     

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.