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Journal: Journal of pharmaceutical sciences


Amorphous drug dispersions are frequently employed to enhance solubility and dissolution of poorly water-soluble drugs and thereby increase their oral bioavailability. Because these systems are metastable, phase separation of the amorphous components and subsequent drug crystallization may occur during storage. Computational methods to determine the likelihood of these events would be very valuable, if their reliability could be validated. This study investigates amorphous systems of indomethacin (IMC) in poly(vinylpyrrolidone) (PVP) and their molecular interactions by means of molecular dynamics (MD) simulations. IMC and PVP molecules were constructed using X-ray diffraction data, and force-field parameters were assigned by analogy with similar groups in Amber-ff03. Five assemblies varying in PVP and IMC composition were equilibrated in their molten states then cooled at a rate of 0.03 K/ps to generate amorphous glasses. Prolonged aging dynamic runs (100 ns) at 298 K and 1 bar were then carried out, from which solubility parameters, the Flory-Huggins interaction parameter, and associated hydrogen bonding properties were obtained. Calculated glass transition temperature (T(g) ) values were higher than experimental results because of the faster cooling rates in MD simulations. Molecular mobility as characterized by atomic fluctuations was substantially reduced below the T(g) with IMC-PVP systems exhibiting lower mobilities than that found in amorphous IMC, consistent with the antiplasticizing effect of PVP. The number of IMC-IMC hydrogen bonds (HBs) formed per IMC molecule was substantially lower in IMC-PVP mixtures, particularly the fractions of IMC molecules involved in two or three HBs with other IMC molecules that may be potential precursors for crystal growth. The loss of HBs between IMC molecules in the presence of PVP was largely compensated for by the formation of IMC-PVP HBs. The difference (6.5 MPa(½) ) between the solubility parameters in amorphous IMC (25.5 MPa(½) ) and PVP (19.0 MPa(½) ) suggests a small, positive free energy of mixing, although it is close to the criterion for miscibility (<7 MPa(1/2) ). In contrast to the solubility-parameter method, the calculated Flory-Huggins interaction parameter (-0.61 ± 0.25), which takes into account the IMC-PVP interaction energy, predicts complete miscibility at all PVP compositions, in agreement with experimental observations. These results from MD simulations were combined with experimental values for the crystalline γ-polymorph of IMC and amorphous IMC to estimate the solubility of IMC in amorphous PVP dispersions and the theoretical enhancement in the aqueous solubility of IMC molecularly dispersed in PVP at various volume fractions. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.

Concepts: Hydrogen bond, Chemistry, Molecular dynamics, Chemical bond, Atom, Glass transition, Glass, Oxygen


Polyethylene glycol (PEG) has been used widely in liposomal formulations as a strategy to inhibit opsonization by plasma proteins and to prolong liposome plasma circulation time. PEG can be incorporated onto the surface of liposomes either during the spontaneous self-assembling process or inserted after vesicle formation. The advantages of employing the PEG postinsertion method include improved drug encapsulation efficiency and the ability to incorporate PEG conjugates for enhanced cell binding and uptake. In this study, we propose to evaluate a cationic lipid nanoparticle formulation containing two PEGylation steps: pre- and post-siRNA insertion. Our results indicate that formulations consisting of the extra PEG post-insertion step significantly increased siRNA circulation in the plasma by two-folds in comparison with the formulations consisting of only the single PEGylation step. Moreover, this formulation was able to efficiently carry siRNA to the tumor site, increase siRNA stability and significantly downregulate luciferase mRNA expression by >50% when compared with the controls in an intraperitoneal and subcutaneous breast cancer tumor model. Overall, our cationic lipid nanoparticle formulation displayed enhanced plasma circulation, reduced liver accumulation, enhanced tumor targeting, and effective gene knockdown–demonstrating excellent utility for the delivery of siRNA. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:227-236, 2013.

Concepts: Lipofection, Gene expression, Protein, Liposome, Messenger RNA, Polymersome, Doxorubicin, Cancer


The physical/chemical stability and potential interactions after diluting two immunoglobulin G1 monoclonal antibodies (mAb), pertuzumab (Perjeta®) and trastuzumab (Herceptin®), in a single intravenous (i.v.) infusion bag containing 0.9% saline (NaCl) solution was evaluated. As commercial products, pertuzumab and trastuzumab are administered through i.v. infusion to patients sequentially, that is, one drug after the other. To increase convenience and minimize the in-clinic time for patients, the compatibility of coadministering pertuzumab (420 and 840 mg) mixed with either 420 or 720 mg trastuzumab, respectively, in a single 250 mL polyolefin or polyvinyl chloride i.v. bag stored for up to 24 h at 5°C or 30°C was determined. The controls (i.e., pertuzumab alone in an i.v. bag, trastuzumab alone in an i.v. bag) and the mAb mixture were assessed using color, appearance, and clarity, concentration, and turbidity by ultraviolet spectroscopy, particulate analysis by light obscuration, size-exclusion chromatography, capillary electrophoresis-sodium dodecyl sulfate, analytical ultracentrifugation, and ion-exchange chromatography. Additionally, capillary zone electrophoresis, imaged capillary isoelectric focusing, and potency were utilized to measure the stability of the admixtures containing 1:1 mixtures of pertuzumab/trastuzumab and their respective controls (420 mg pertuzumab alone and 420 mg trastuzumab alone). No observable differences were detected by the above methods in the pertuzumab/trastuzumab mixtures stored up to 24 h at either 5°C or 30°C. The physicochemical methods as listed above were able to detect both molecules as well as the minor variants in the drug mixture, even though some overlap of mAb species were seen in the chromatograms and electropherograms. Furthermore, biophysical analysis also did not show any interactions between the two mAbs or any physical instability under these conditions. Additionally, the drug mixture tested by the pertuzumab-specific inhibition of cell proliferation bioassay showed comparable potency before and after storage. On the basis of these results, pertuzumab and trastuzumab admixture in a single i.v. bag is physically and chemically stable for up to 24 h at 5°C or 30°C and can be used for clinical administration. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.

Concepts: Micellar electrokinetic chromatography, Capillary electrophoresis, Affinity electrophoresis, Mixture, Electrophoresis, Gel electrophoresis, Chromatography, Monoclonal antibodies


Content uniformity (CU) of tablets is a critical property that needs to be well controlled in pharmaceutical products. Methods that predict the CU accurately can greatly help in reducing the development efforts. This article presents a statistical mechanical framework for predicting CU based on first principles at the molecular level. The tablet is modeled as an open system that can be treated as a grand canonical ensemble to calculate fluctuations in the number of granules and thus the CU. Exact analytical solutions to hard sphere mixture systems are applied to derive an expression for the CU and elucidate the different factors that impact CU. The model was tested against literature data and a large set of tablet formulations specifically made and analyzed for CU using a model active pharmaceutical ingredient. The formulations covered the effect of granule size, percentage loading, and tablet weight on the CU. The model is able to predict the mean experimental coefficient of variation (CV) with good success and captures all the elements that impact the CU. The predictions of the model serve as a theoretical lower limit for the mean CV (for infinite batches or tablets) that can be expected during manufacturing assuming the best processing conditions. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:4501-4515, 2012.

Concepts: Futurology, Prediction, Excipient, Pharmaceutical formulation, Tablet, Scientific method, Pharmacology


In this paper, we present an investigation of the polymorphism of griseofulvin. In addition to the only reported crystalline form (form I), two new polymorphic forms (II and III) have been identified and characterized by differential scanning calorimetry and powder X-ray diffraction. Reasons why these two polymorphs were isolated during the present study, but not detected during the numerous previous studies on this drug, are also discussed. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.

Concepts: Crystallization, Powder diffraction, Diffraction, X-ray, Crystal, Differential scanning calorimetry, Materials science, Crystallography


Amorphous matrices, composed of sugars, are markedly plasticized by moisture uptake, which results in physical instability. Our previous studies, in the compression pressure range ≤443 MPa, indicated that when a matrix is compressed, the amount of sorbed water at given relative humidities (RHs) decreases, whereas the glass transition temperature (Tg ) remains constant. Herein, the effect of higher compression pressures than those used previously was explored to investigate the feasibility of using compression to improve the physical stability of amorphous sugar matrix against water uptake and subsequent collapse. Amorphous sugar samples were prepared by freeze-drying and then compressed at 0-665 MPa, followed by rehumidification at given RHs. The physical stability of the amorphous sugar sample was evaluated by measuring Tg and crystallization temperature (Tcry ). The amounts of sorbed water, different in the interaction state, were determined using an FTIR technique. It was found that the compression at pressures of ≥443 MPa decreased the amount of sorbed water, which is a major factor in plasticization and crystallization, and thus markedly increased the Tg and Tcry relative to that for the uncompressed sample. Hence, the compression at several hundreds MPa appears to be feasible for improving the physical stability of amorphous sugar matrix. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.

Concepts: Pressure, Physics of glass, Compression, Vacuum, Amorphous solid, Liquid, Glass, Glass transition


Nanotechnology is a promising alternative to overcome the limitations of classical chemotherapy. As a novel approach, dendrimer-coated magnetic nanoparticles (DcMNPs) maintain suitable drug delivery system because of their buildup of functional groups, symmetry perfection, nanosize, and internal cavities. They can also be targeted to the tumor site in a magnetic field. The aim of this study is to obtain an effective targeted delivery system for doxorubicin, using polyamidoamine (PAMAM) DcMNPs. Different generations (G2 , G3 , G4 , and G7 ) of PAMAM DcMNPs were synthesized. Doxorubicin loading, release, and stability efficiencies in these nanoparticles (NPs) were studied. The results showed that low-generation NPs obtained in this study have pH-sensitive drug release characteristics. G4 DcMNP, which releases most of the drug in lower pH, seems to be the most suitable generation for efficient Doxorubicin delivery. Furthermore, application of doxorubicin-loaded G4 DcMNPs may help to overcome doxorubicin resistance in MCF-7 cells. On the contrary, G2 and G3 DcMNPs would be suitable for the delivery of drugs such as vinca alkaloids (Johnson IS, Armstrong JG, Gorman M, Burnett JP. 1963. Cancer Res 23:1390-1427.) and taxenes (Clarke SJ, Rivory LP. 1999. Clin Pharmacokinet 36(2):99-114.), which show their effects in cytoplasm. The results of this study can provide new insights in the development of pH-sensitive targeted drug delivery systems to overcome drug resistance during cancer therapy. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.

Concepts: Oncology, Targeted drug delivery, Magnetic field, Drugs, Pharmacology, Nanotechnology, Drug delivery, Chemotherapy


We previously reported that combined fluoxetine administration at antidepressant doses renders additive antidepressant effects, whereas non-antidepressant doses potentiate the omega-3 fatty acid antidepressant effect. In the present study, we aimed to evaluate putative pharmacokinetic and brain omega-3 fatty acid-related aspects for fluoxetine potentiation of omega-3 fatty acid antidepressant effect in rats. Coadministration of omega-3 fatty acids with a non-antidepressant dose of fluoxetine (1 mg/kg day) failed to affect both brain fluoxetine concentration and norfluoxetine plasma concentration profile. Fluoxetine plasma concentrations remained below the sensitivity limit of the detection method. Either antidepressant (10 mg/kg day) or non-antidepressant (1 mg/kg day) doses of fluoxetine in combination with omega-3 fatty acids increased hippocampal docosapentaenoic acid (DPA, 22:5 omega-3) levels. Although individual treatments had no effects on DPA concentration, DPA increase was higher when omega-3 were combined with the non-antidepressant dose of fluoxetine. Chronic DPA administration exerted antidepressant-like effects in the forced swimming test while increasing hippocampal docosahexaenoic (22:6 omega-3) and DPA levels. Our results suggest no pharmacokinetic interaction and reveal specific hippocampal DPA changes after fluoxetine and omega-3 combined treatments in our experimental conditions. The DPA role in the synergistic effect of fluoxetine and omega-3 combined treatments will be for sure the focus of future studies. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.

Concepts: Triglyceride, Docosahexaenoic acid, Fatty acids, Eicosapentaenoic acid, Docosapentaenoic acid, Omega-6 fatty acid, Fatty acid, Omega-3 fatty acid


The use of co-solvent systems has been demonstrated to shorten lengthy freeze drying processes and improve the solubility and stability of certain active pharmaceutical ingredients. The goal of the present study was to evaluate the suitability of two thermal characterization techniques, differential scanning calorimetry and freeze dry microscopy, to identify an optimal co-solvent system. Binary mixtures of a co-solvent (tert-butanol, dimethyl sulfoxide, 1,4-dioxane, acetone or ethanol) and water were investigated. Ternary mixtures of frequently used excipients (50 mg/g mannitol, sucrose, glycine or polyvinylpyrrolidone) and a solvent-water system were then analyzed for their thermal properties. PVP presented a particularly high glass transition temperature (Tg') in 70% TBA at -17.9°C. Large needle-shaped crystals that have been shown to be associated with improved processability were observed with mannitol and PVP in 40% 1,4-dioxane. A heterogeneous sublimation rate of the solvent and water whose impact on product stability remained unclear was observed with PVP in 40% 1,4-dioxane. FDM analysis demonstrated a possible extension of the process time for PVP in 99% DMSO due to a slowly moving sublimation front. Conceivable negative consequences and the need for special treatment for low melting co-solvents, such as ethanol and acetone, were predicted and discussed.

Concepts: Food preservation, Materials science, Melting point, Sublimation, Glass transition, Solvent, Freeze drying, Differential scanning calorimetry


Parenteral products should aim toward being isotonic and euhydric (physiological pH). Yet, due to other considerations, this goal is often not reasonable or doable. There are no clear allowable ranges related to pH and osmolality, and thus, the objective of this review was to provide a better understanding of acceptable formulation pH, buffer strength, and osmolality taking into account the administration route (i.e., intramuscular, intravenous, subcutaneous) and administration technique (i.e., bolus, push, infusion). This evaluation was based on 3 different approaches: conventional, experimental, and parametric. The conventional way of defining formulation limits was based on standard pH and osmolality ranges. Experimental determination of titratable acidity or in vitro hemolysis testing provided additional drug product information. Finally, the parametric approach was based on the calculation of theoretical values such as (1) the maximal volume of injection which cannot shift the blood’s pH or its molarity out of the physiological range and (b) a dilution ratio at the injection site and by verifying that threshold values are not exceeded. The combination of all 3 approaches can support the definition of acceptable pH, buffer strength, and osmolality of formulations and thus may reduce the risk of failure during preclinical and clinical development.

Concepts: Acid, Routes of administration, Bolus, Intravenous therapy, Dosage form, PH, Pharmacology, Route of administration