Efavirenz Dissolution Enhancement IV—Antisolvent Nanocrystallization by Sonication,Physical Stability,and Dissolution

Efavirenz is a fundamental drug in the HIV therapy; however, it has a low bioavailability due to low water solubility. Particle nanonization should enhance its dissolution and therefore its bioavailability. Nanocrystallization is a promising technique for preparing drug nanocrystals. A solution containing efavirenz (EFV) and methanol was added to an aqueous solution of particle stabilizers, under sonication. The adequate polymer stabilizer and its concentration and drug load were evaluated. Particle size and zeta potential of suspensions were measured. Nanosuspensions were freeze-dried and the resulting powder was characterized by some techniques, with special attention to dissolution. Particle size and zeta potential analysis showed that HMPC and PVP were the most suitable polymers. All samples prepared with these stabilizers had nanosized particles and proper zeta potential; however, sedimentation and particle growth were detected with Turbiscan?. Time-related destabilization occurred when the lowest polymer concentration of 20% was used. SEM analysis of the dried powder shows film formation for suspensions with 40% of polymer and particle aggregation in samples with less polymer. Dissolution profiles of samples were higher than EFV raw material, although the lower the polymer concentration, the higher the dissolution.     

In vitro evaluation of a morphine polymeric complex: Flowability behavior and dissolution study

The purpose of this research was to perform a granulometrical and flow properties study of a morphine polymeric complex and determine the influence of 3 variables—particle size of complex, pH value, and ionic strength of the dissolution medium—on the dissolution behavior. The morphine-Eudragit L complex was produced in aqueous medium from morphine hydrochloride saturated solution and Eudragit L 30D diluted until 12% wt/vol and partially neutralized (40%). To determine the rheological behavior of the complex, several rheological tests were developed: bulk and tapped densities, Hausner ratio, angle of repose, and flow rate. The results corresponding to the technological study suggest that the 100- to 250-μm fraction can be considered as free flowing powder. In relation to the dissolution behavior of the complex, the results indicate that the ionic strength has been detected as the most influencing factor when values below physiological conditions are used. In conclusion, no technological problems for the production of further solid dosage forms are expected. Furthermore, no changes in the dissolution profiles of the complex have been detected when ionic strength values are inside the physiological range.     

Drop-on-Demand System for Manufacturing of Melt-based Solid Oral Dosage: Effect of Critical Process Parameters on Product Quality

The features of a drop-on-demand-based system developed for the manufacture of melt-based pharmaceuticals have been previously reported. In this paper, a supervisory control system, which is designed to ensure reproducible production of high quality of melt-based solid oral dosages, is presented. This control system enables the production of individual dosage forms with the desired critical quality attributes: amount of active ingredient and drug morphology by monitoring and controlling critical process parameters, such as drop size and product and process temperatures. The effects of these process parameters on the final product quality are investigated, and the properties of the produced dosage forms characterized using various techniques, such as Raman spectroscopy, optical microscopy, and dissolution testing. A crystallization temperature control strategy, including controlled temperature cycles, is presented to tailor the crystallization behavior of drug deposits and to achieve consistent drug morphology. This control strategy can be used to achieve the desired bioavailability of the drug by mitigating variations in the dissolution profiles. The supervisor control strategy enables the application of the drop-on-demand system to the production of individualized dosage required for personalized drug regimens.     

Excipient Stability in Oral Solid Dosage Forms: A Review

The choice of excipients constitutes a major part of preformulation and formulation studies during the preparation of pharmaceutical dosage forms. The physical, mechanical, and chemical properties of excipients affect various formulation parameters, such as disintegration, dissolution, and shelf life, and significantly influence the final product. Therefore, several studies have been performed to evaluate the effect of drug-excipient interactions on the overall formulation. This article reviews the information available on the physical and chemical instabilities of excipients and their incompatibilities with the active pharmaceutical ingredient in solid oral dosage forms, during various drug-manufacturing processes. The impact of these interactions on the drug formulation process has been discussed in detail. Examples of various excipients used in solid oral dosage forms have been included to elaborate on different drug-excipient interactions.     

The role of particle size distribution on bioavailability of cyclosporine: novel drug delivery system

During the long period of cyclosporine-containing dosage forms development a lot of significant findings have been done especially in the field of drug delivery systems. Currently available drugs are based, from technological point of view, on self-dispersible drug delivery systems, which contain cyclosporine solved in pharmaceutically acceptable vehicle. One can find difference among particular systems a) at particle size distribution after dispergation, b) at composition and c) at bioavailability of cyclosporine. As far as improvement of bioavailability between original brand leader formulation Sandimmune and recent brand leader formulation Neoral was followed by significant improvement in particle size distribution it was generally assumed that the reason for this improvement have been found. Several other formulations e.g. Consupren or SangCyA--self-dispersible systems, more or less correspond with above mentioned theory that smaller is better and by this principle bridged liquid based dosage forms with solid dosage forms. Bioavailability of novel drug delivery system which gives coarse dispersion with average particle size between 1-150 microns when dispersed have been tested on healthy volunteers. No difference among pharmacokinetic parameters of novel drug delivery system and microemulsion system have been observed in spite of fact that average particle size of novel system is almost 1000x bigger.     

In Vitro Dissolution of Generic Immediate-Release Solid Oral Dosage Forms Containing BCS Class I Drugs: Comparative Assessment of Metronidazole,Zidovudine, and Amoxicillin Versus Relevant Comparator Pharmaceutical Products in South Africa and India

Biowaivers are recommended for immediate-release solid oral dosage forms using dissolution testing as a surrogate for in vivo bioequivalence studies. Several guidance are currently available (the World Health Organization (WHO), the US FDA, and the EMEA) where the conditions are described. In this study, definitions, criteria, and methodologies according to the WHO have been applied. The dissolution performances of immediate-release metronidazole, zidovudine, and amoxicillin products purchased in South African and Indian markets were compared to the relevant comparator pharmaceutical product (CPP)/reference product. The dissolution performances were studied using US Pharmacopeia (USP) apparatus 2 (paddle) set at 75 rpm in each of three dissolution media (pH1.2, 4.5, and 6.8). Concentrations of metronidazole, zidovudine, and amoxicillin in each dissolution media were determined by HPLC. Of the 11 metronidazole products tested, only 8 could be considered as very rapidly dissolving products as defined by the WHO, whereas 2 of those products could be considered as rapidly dissolving products but did not comply with the f₂ acceptance criteria in pH 6.8. All 11 zidovudine products were very rapidly dissolving, whereas in the case of the 14 amoxicillin products tested, none of those products met any of the WHO criteria. This study indicates that not all generic products containing the same biopharmaceutics classification system (BCS) I drug and in similar strength and dosage form are necessarily in vitro equivalent. Hence, there is a need for ongoing market surveillance to determine whether marketed generic products containing BCS I drugs meet the release requirements to confirm their in vitro bioequivalence to the respective reference product.KEY WORDS: BCS, dissolution testing, generic drug, immediate-release solid oral dosage forms, WHO criteria     

Nanosuspensions Containing Oridonin/HP-β-Cyclodextrin Inclusion Complexes for Oral Bioavailability Enhancement via Improved Dissolution and Permeability

Chemotherapy via oral route of anticancer drugs offers much convenience and compliance to patients. However, oral chemotherapy has been challenged by limited absorption due to poor drug solubility and intestinal efflux. In this study, we aimed to develop a nanosuspension formulation of oridonin (Odn) using its cyclodextrin inclusion complexes to enhance oral bioavailability. Nanosuspensions containing Odn/2 hydroxypropyl-β-cyclodextrin inclusion complexes (Odn-CICs) were prepared by a solvent evaporation followed by wet media milling technique. The nanosuspensions were characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), and dissolution. The resulting nanosuspensions were approximately 313.8 nm in particle size and presented a microcrystal morphology. Nanosuspensions loading Odn-CICs dramatically enhanced the dissolution of Odn. Further, the intestinal effective permeability of Odn was markedly enhanced in the presence of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and poloxamer. Bioavailability studies showed that nanosuspensions with Odn-CICs can significantly promote the oral absorption of Odn with a relative bioavailability of 213.99% (Odn suspensions as reference). Odn itself possesses a moderate permeability and marginal intestinal metabolism. Thus, the enhanced bioavailability for Odn-CIC nanosuspensions can be attributed to improved dissolution and permeability by interaction with absorptive epithelia and anti-drug efflux. Nanosuspensions prepared from inclusion complexes may be a promising approach for the oral delivery of anticancer agents.     

Solution-Mediated Phase Transformation of Haloperidol Mesylate in the Presence of Sodium Lauryl Sulfate

Forming a salt is a common way to increase the solubility of a poorly soluble compound. However, the solubility enhancement gained by salt formation may be lost due to solution-mediated phase transformation (SMPT) during dissolution. The SMPT of a salt can occur due to a supersaturated solution near the dissolving surface caused by pH or other solution conditions. In addition to changes in pH, surfactants are also known to affect SMPT. In this study, SMPT of a highly soluble salt, haloperidol mesylate, at pH 7 in the presence of a commonly used surfactant, sodium lauryl sulfate (SLS), was investigated. Dissolution experiments were performed using a flow-through dissolution apparatus with solutions containing various concentrations of SLS. Compacts of haloperidol mesylate were observed during dissolution in the flow-through apparatus using a stereomicroscope. Raman microscopy was used to characterize solids. The dissolution of haloperidol mesylate was significantly influenced by the addition of sodium lauryl sulfate. In conditions where SMPT was expected, the addition of SLS at low concentrations (0.1–0.2 mM) reduced the dissolution of haloperidol mesylate. In solutions containing concentrations of SLS above the critical micelle concentration (CMC) (10–15 mM), the dissolution of haloperidol mesylate increased compared to below the CMC. The solids recovered from solubility experiments of haloperidol mesylate indicated that haloperidol free base precipitated at all concentrations of SLS. Above 5 mM of SLS, Raman microscopy suggested a new form, perhaps the estolate salt. The addition of surfactant in solids that undergo solution-mediated phase transformation can add complexity to the dissolution profiles and conversion.     

Pluronic and Tetronic Copolymers with Polyglycolyzed Oils as Self-Emulsifying Drug Delivery Systems

The potential of poly(ethylene oxide)-poly(propylene oxide) block copolymers Pluronic F127 (PF127) and Tetronic 304 (T304), 904 (T904) and 1307 (T1307) as components of solid self-(micro)emulsifying dosage forms, S(M)EDDS, was evaluated. The dependence of the self-associative properties of Tetronics on pH explained the low ability of the micelles to solubilize griseofulvin at acid pH (sevenfold increase) compared to at alkaline pH (12-fold). Blends of polyglycolyzed glycerides (Labrasol, Labrafac CC, and Labrafil M 1944CS) with each copolymer at two different weight ratios (80:20 and 60:40) were prepared, diluted in water, and characterized in terms of globule size, appearance and griseofulvin solubility. The blends with Labrasol led to microemulsions that are able to increase drug solubility up to 30-fold. SMEDD hard gelatine capsules filled with griseofulvin and Labrasol or Labrasol/copolymer 80:20 showed a remarkable increase in drug solubility and dissolution rate, particularly when T904, T1307 or PF127 was present in the blend. This effect was more remarkable when the volume of the dissolution medium was 200 ml (compared to 900 ml), which can be related to a higher stability of the microemulsion when there is a greater concentration of the copolymer and glyceride in the medium.     

Evaluation of Tadalafil Nanosuspensions and Their PEG Solid Dispersion Matrices for Enhancing Its Dissolution Properties

The aim of this work was to prepare and evaluate Tadalafil nanosuspensions and their PEG 4000 solid dispersion matrices to enhance its dissolution rate. Nanosuspensions were prepared by precipitation/ultrasonication technique at 5°C where different stabilizers were screened for stabilization. Nanosuspensions were characterized in terms of particle size and charge. Screening process limited suitable stabilizers into structurally related surfactants composed of a mixture of Tween80 and Span80 at 1:1 ratio (in percent, weight/volume) in adjusted alkaline pH (named TDTSp-OH). The surfactant mixture aided the production of nanosuspensions with an average particle size of 193 ± 8 nm and with short-term stability sufficient for further processing. Solid dispersion matrices made of dried Tadalafil nanosuspensions or dried Tadalafil raw powder suspensions and PEG 4000 as a carrier were prepared by direct compression. Drying was performed via dry heat or via freeze dry. Drug release studies showed that, in general, tablet formulations made of freeze-dried product exhibited faster initial release rates than the corresponding tablets made of oven-dried products which could be attributed to possible larger crystal growth and larger crushing strengths of oven-dried formulations. At best, 60% of drug was released from solid dispersion matrices, while more than 90% of drug was released from TDTSp-OH nanosuspension within the first 5 min. In conclusion, Tadalafil nanosuspensions obtained using a mixed surfactant system provided rapid dissolution rates of Tadalafil that can theoretically enhance its bioavailability.KEY WORDS: nanosuspension, particle size, solid dispersion, stabilizer, tablets, Tadalafil     

Role of surfactant and pH on dissolution properties of fenofibrate and glipizide—A technical note

Depending on the dose size and solubility characteristics of low solubility drugs, a meaningful and discriminatory power of dissolution rate testing can be demonstrated. Saturation solubility of fenofibrate and glipizide in different media were determined. Solubility of fenofibrate increased directly with SLS concentration. For a 54-mg fenofibrate tablet, SLS at 0.025 M level is required for a discriminative dissolution test, while for 160-mg tablet, dissolution condition and levels of SLS should be optimized; higher concentrations may be effective (ie, 0.052 M, ∼1.5%). A pH 6.8 phosphate buffer medium is appropriate for glipizide 10-mg tablet dissolution study, when formulation ingredients include excipients with surface activity (eg, HPMC).     

Investigation on drug dissolution and particle characteristics of pellets related to manufacturing process variables of high-shear granulation

There is a growing interest for multiparticulate solid dosage forms such as pellets, because of their several advantages over tablets during drug therapy. It is essential to investigate the drug dissolution process which can be influenced by the composition and manufacturing process technology, too. This study was performed applying experimental design in order to evaluate the effects of independent process variables during high-shear pelletisation, taking the impeller speed (x1) and granulation binder flow rate (x2) as factors into consideration. Theophylline containing pellet formulation was prepared using a matrix consisted of ethylcellulose, microcrystalline cellulose and lactose. Dissolution profiles were modeled by the Weibull function to evaluate the power of process variables. Both process variables were powerful to influence the particle agglomeration. A linear regression was found between the particle size and the diffuse reflectance values after the Kubelka-Munk transformation. Differences in the diffuse reflectance spectra of pellet samples related to particle size offer a fast instrumental method for the in-process control.     

An Automated System for Monitoring and Regulating the pH of Bicarbonate Buffers

The bicarbonate buffer is considered as the most biorelevant buffer system for the simulation of intestinal conditions. However, its use in dissolution testing of solid oral dosage forms is very limited. The reason for this is the thermodynamic instability of the solution containing hydrogen carbonate ions and carbonic acid. The spontaneous loss of carbon dioxide (CO₂) from the solution results in an uncontrolled increase of the pH. In order to maintain the pH on the desired level, either a CO₂ loss must be completely avoided or the escaped CO₂ has to be replaced by quantitative substitution, i.e. feeding the solution with the respective amount of gas, which re-acidifies the buffer after dissociation. The present work aimed at the development of a device enabling an automatic pH monitoring and regulation of hydrogen carbonate buffers during dissolution tests.     

Rapid expansion from supercritical to aqueous solution to produce submicron suspensions of water-insoluble drugs

Stable suspensions of submicron particles of cyclosporine, a water-insoluble drug, have been produced by rapid expansion from supercritical to aqueous solution (RESAS). To minimize growth of the cyclosporine particles, which would otherwise occur in the free jet expansion, the solution was sprayed into an aqueous Tween-80 (Polysorbate-80) solution. Steric stabilization by the surfactant impedes particle growth and agglomeration. The particles were an order of magnitude smaller than those produced by RESS into air without the surfactant solution. Concentrations as high as 38 mg/mL for 400-700 nm particles were achieved in a 5.0% (w/w) Tween-80 solution.     

The Preparation and Evaluation of Water-Soluble SKLB610 Nanosuspensions with Improved Bioavailability

The aim of the study was to investigate the potential of nanosuspension to enhance the bioavailability of SKLB610 (Biopharmaceutical Classification System class II drug), a bioactive anticancer compound synthesized in our labs. SKLB610 nanosuspensions were prepared using wet media milling. Physicochemical characteristics of the nanosuspensions were evaluated, including particle size and distribution, dissolution, transmission electron microscopy, atomic force microscopy, thermogravimetric analysis, and X-ray powder diffractometry. The dissolution rate of SKLB610 was greatly improved in nanosuspensions, compared to crude SKLB610. Pharmacokinetic studies in rats demonstrated that the oral bioavailability of SKLB610 in nanosuspension (89.4%) was 2.6-fold higher than in coarse suspension (34.1%). Stabilizer type, milling time, and milling speed had a significant effect on particle size of the SKLB610 nanosuspensions. Nanosuspensions effectively improved the dissolution rate and bioavailability of the water-insoluble drug SKLB610 by reducing the compound particle size to the nanoscale and employing a proper formulation.     

Dissolution Properties and Physical Characterization of Telmisartan–Chitosan Solid Dispersions Prepared by Mechanochemical Activation

Solid dispersion systems of telmisartan (a poorly water-soluble antihypertension drug) with biopolymer carrier chitosan have been investigated in this study. The mechanism of solubilization of chitosan for drug has been studied. In addition, the influence of several factors was carefully examined, including the preparation methods, the drug/carrier weight ratios, and the milling time. Drug dissolution and physical characterization of different binary systems were studied by in vitro dissolution test, particle size distribution, Fourier transform infrared spectroscopy, differential scanning calorimetry, powder X-ray diffractometry, and scanning electron microscopy. The results presented that the weak basic property of chitosan appeared as the main driving force for the drug dissolution enhancement. Other effects such as decreased drug crystallinity and size played a positive contributory role. Among the preparation methods, cogrinding was the best method showing strong drug amorphization, reduced particle size, and enhanced dissolution. The drug dissolution markedly improved with increasing the amount of chitosan in solid mixtures. As a result, a significant effect of chitosan increasing telmisartan dissolution has been demonstrated, and cogrinding in a roll ball mill was the best way to prepare solid dispersions, which had high degree of uniformity in drug content and had a practical application in manufacturing.     

Enhancing and Sustaining AMG 009 Dissolution from a Bilayer Oral Solid Dosage Form via Microenvironmental pH Modulation and Supersaturation

Enhancing and sustaining AMG 009 dissolution from a matrix tablet via microenvironmental pH modulation and supersaturation, where poorly soluble acidic AMG 009 molecule was intimately mixed and compressed together with a basic pH modifier (e.g., sodium carbonate) and nucleation inhibitor hydroxypropyl methylcellulose K100 LV (HPMC K100 LV), was demonstrated previously. However, not all acidic or basic drugs are compatible with basic or acidic pH modifiers either chemically or physically. The objective of this study is to investigate whether similar dissolution enhancement of AMG 009 can be achieved from a bilayer dosage form, where AMG 009 and sodium carbonate are placed in a separate layer with or without the addition of HPMC K100 LV in each layer. Study results indicate that HPMC K100 LV-containing bilayer dosage forms gained similar dissolution enhancement as matrix dosage forms did. Bilayer dosage forms without HPMC K100 LV benefitted the least from dissolution enhancement.     

Enhancement of Bioavailability of Cefpodoxime Proxetil Using Different Polymeric Microparticles

Poorly water-soluble drugs such as cefpodoxime proxetil (400 μg/ml) offer a challenging problem in drug formulation as poor solubility is generally associated with poor dissolution characteristics and thus poor oral bioavailability. According to these characteristics, preparation of cefpodoxime proxetil microparticle has been achieved using high-speed homogenization. Polymers (methylcellulose, sodium alginate, and chitosan) were precipitated on the surface of cefpodoxime proxetil using sodium citrate and calcium chloride as salting-out agents. The pure drug and the prepared microparticles with different concentrations of polymer (0.05–1.0%) were characterized in terms of solubility, drug content, particle size, thermal behavior (differential scanning calorimeter), surface morphology (scanning electron microscopy), in vitro drug release, and stability studies. The in vivo performance was assessed by pharmacokinetic study. The dissolution studies demonstrate a marked increase in the dissolution rate in comparison with pure drug. The considerable improvement in the dissolution rate of cefpodoxime proxetil from optimized microparticle was attributed to the wetting effect of polymers, altered surface morphology, and micronization of drug particles. The optimized microparticles exhibited excellent stability on storage at accelerated condition. The in vivo studies revealed that the optimized formulations provided improved pharmacokinetic parameter in rats as compared with pure drug. The particle size of drug was drastically reduced during formulation process of microparticles.     

Design,Optimization, and Evaluation of Lurasidone Hydrochloride Nanocrystals

The present investigation was carried out to design, optimize, and evaluate lurasidone hydrochloride nanocrystals for improving its solubility and dissolution characteristics. Nanocrystals were prepared by media milling technique using zirconium oxide beads with 0.1 mm diameter. Various stabilizers, viz. poloxamer 188, PVP K30, SLS, HPMC E15, and PVP S 630 D, were evaluated to stabilize the nanocrystals. The Pareto chart obtained through Plackett-Burman screening design revealed that HPMC E 15 showed the highest standardized effect (p value <0.05) on percent dissolution efficiency at 2 min. In subsequent studies, a 3² factorial design was employed to quantify the effect of two independent variables, namely amount of stabilizer and milling time on predetermined response variables mean particle size, saturation solubility, and percent dissolution efficiency at 2 min. Statistical analysis of the factorial design revealed that all predetermined response variables were significantly dependent (p value <0.05) on the independent variables. The observed response of the optimized batch prepared as per the desirability function was in close agreement with predicted response, and mathematical model generated was validated. The optimized batch was lyophilized, and X-ray powder diffraction studies indicated that there was no substantial change in crystallinity of the drug. The optimized formulation showed mean particle size of 228 nm and released almost all the drug within first 5 min. Since the crystallinity of the drug is maintained, improvement in saturation solubility and dissolution efficiency could be attributed to decrease in mean particle size of the drug.     

Phospholipid-stabilized nanoparticles of cyclosporine a by rapid expansion from supercritical to aqueous solution

The purpose of this research was to form stable suspensions of submicron particles of cyclosporine A, a water-insoluble drug, by rapid expansion from supercritical to aqueous solution (RESAS). A solution of cyclosporine A in CO₂ was expanded into an aqueous solution containing phospholipid vesicles mixed with nonionic surfactants to provide stabilization against particle growth resulting from collisions in the expanding jet. The products were evaluated by measuring drug loading with high performance liquid chromatography (HPLC), particle sizing by dynamic light scattering (DLS), and particle morphology by transmission electron microscopy (TEM) and x-ray diffraction. The ability of the surfactant molecules to orient at the surface of the particles and provide steric stabilization could be manipulated by changing process variables including temperature and suspension concentration. Suspensions with high payloads (up to 54 mg/mL) could be achieved with a mean diameter of 500 nm and particle size distribution ranging from 40 to 920 nm. This size range is several hundred nanometers smaller than that produced by RESAS for particles stabilized by Tween 80 alone. The high drug payloads (≈10 times greater than the equilibrium solubility), the small particle sizes, and the long-term stability make this process attractive for development.