A prediction system: Regulating effect of small-molecule additives on properties of amorphous solid dispersions prepared by hot-melt extrusion technology.

Amorphous solid dispersions (ASDs) with solubility advantage are suffering from the recrystallization risk and subsequent reduced dissolution triggered by high hygroscopicity of hydrophilic polymers and the supersaturation of ASD solutions. To address these issues, in this study, small-molecule additives (SMAs) in the Generally Recognized as Safe (GRAS) list were introduced into drug-polymer ASD. For the first time, we systematically revealed the intrinsic correlation between SMAs and properties of ASDs at the molecular level and constructed a prediction system for the regulation of properties of ASDs. The types and dosages of SMAs were screened by Hansen solubility and Flory-Huggins interaction parameters, as well as differential scanning calorimetry. X-ray photoelectron spectroscopy and adsorption energy (Eabs) calculation showed that the surface group distribution of ASDs and Eabs between ASD system and solvent were vital factors affecting the hygroscopicity and then stability. The radial distribution function revealed that interactions between components were proposed to be the critical factor for the dissolution performance. Based on this, a prediction system for regulating the properties of ASDs was successfully constructed mainly via molecular dynamics simulations and simple solid-state characterizations, and then validated by cases, which efficiently reduces the time and economic cost of pre-screening ASDs.

Interaction of constituents of MDT regimen for leprosy with Mycobacterium leprae HSP18: impact on its structure and function.

Mycobacterium leprae, the causative organism of leprosy, harbors many antigenic proteins, and one such protein is the 18-kDa antigen. This protein belongs to the small heat shock protein family and is commonly known as HSP18. Its chaperone function plays an important role in the growth and survival of M. leprae inside infected hosts. HSP18/18-kDa antigen is often used as a diagnostic marker for determining the efficacy of multidrug therapy (MDT) in leprosy. However, whether MDT drugs (dapsone, clofazimine, and rifampicin) do interact with HSP18 and how these interactions affect its structure and chaperone function is still unclear. Here, we report evidence of HSP18-dapsone/clofazimine/rifampicin interaction and its impact on the structure and chaperone function of HSP18. These three drugs interact efficiently with HSP18 (having submicromolar binding affinity) with 1 : 1 stoichiometry. Binding of these MDT drugs to the 'α-crystallin domain' of HSP18 alters its secondary structure and tryptophan micro-environment. Furthermore, surface hydrophobicity, oligomeric size, and thermostability of the protein are reduced upon interaction with these three drugs. Eventually, all these structural alterations synergistically decrease the chaperone function of HSP18. Interestingly, the effect of rifampicin on the structure, stability, and chaperone function of this mycobacterial small heat shock protein is more pronounced than the other two MDT drugs. This reduction in the chaperone function of HSP18 may additionally abate M. leprae survivability during multidrug treatment. Altogether, this study provides a possible foundation for rational designing and development of suitable HSP18 inhibitors in the context of effective treatment of leprosy.

Effect of XlogP and hansen solubility parameters on the prediction of small molecule modified docetaxel, doxorubicin and irinotecan conjugates forming stable nanoparticles.

Small molecule-chemotherapeutic drug conjugate nanoparticles (SMCDC NPs) has a great advantage in improving drug loading. However, the factors which influence these conjugates forming stable nanoparticles (NPs) are currently unclear. In our previous studies, we synthesized a series of fatty acid-paclitaxel conjugates and suggested that the changes in the hydrophobic parameters (XlogP), solubility parameters and crystallinity of these fatty acid-paclitaxel conjugates were the key factors for affecting these small molecule-chemotherapeutic drug conjugates (SMCDCs) forming stable NPs in water. Here, we selected clinically widely used chemotherapeutic drug (docetaxel (DTX), doxorubicin (DOX) and irinotecan (Ir)) as model drug, and chose three straight-chain fatty acids (acetic acid (Ac), hexanoic acid (HA) and stearic acid (SA)) and one branched small molecule (N-(tert-butoxycarbonyl) glycine (B-G)) to synthesize 12 SMCDCs. Our results indicated that our prediction criterions obtained from paclitaxel conjugates were also appropriated for these synthesized SMCDCs. We suggested that the present studies expanded the scope of application of the above-mentioned influencing factors, provided research ideas for the rational design of SMCDC forming NPs and a basis for screening NPs with good anticancer activity.

On-Demand Reversible UV-Triggered Interpenetrating Polymer Network-Based Drug Delivery System Using the Spiropyran-Merocyanine Hydrophobicity Switch.

A reversible switchable on-demand UV-triggered drug delivery system (DDS) based on interpenetrating polymer networks (IPNs) with silicone as the host polymer and spiropyran (SP)-functionalized guest polymer is designed and demonstrated. The photo-responsive IPNs provide a new triggered drug delivery concept as they exploit the change in intermolecular interactions (work of adhesion) among the drug, matrix, and solvent when the incorporated hydrophobic SP moieties transform into the hydrophilic merocyanine form upon light irradiation without degradation and disruption of the DDS. The change in how the copolymer composition (hydrophilicity and content) and the lipophilicity of the drug (log P) affect the release profile was investigated. A thermodynamic model, based on Hansen solubility parameters, was developed to design and optimize the polymer composition of the IPNs to obtain the most efficient light-triggered drug release and suppression of the premature release. The developed IPNs showed excellent result for dopamine, l-dopa, and prednisone with around 90-95% light-triggered release. The model was applied to study the release behavior of drugs with different log P and to estimate if the light-induced hydrophobic-to-hydrophilic switch can overcome the work of adhesion between polymers and drugs and hence the desorption and release of the drugs. To the best of our knowledge, this is the first time that work of adhesion is used for this aim. Comparing the result obtained from the model and experiment shows that the model is useful for evaluating and estimating the release behavior of specific drugs merocyanine, IPN, DDS, and spiropyran.

Like Dissolves Like? A Comprehensive Evaluation of Partial Solubility Parameters to Predict Polymer-Drug Compatibility in Ultrahigh Drug-Loaded Polymer Micelles.

Despite decades of research, our understanding of the molecular interactions between drugs and polymers in drug-loaded polymer micelles does not extend much beyond concepts such as "like-dissolves-like" or hydrophilic/hydrophobic. However, polymer-drug compatibility strongly affects formulation properties and therefore the translation of a formulation into the clinics. Specific interactions such as hydrogen-bonding, π-π stacking, or coordination interactions can be utilized to increase drug loading. This is commonly based on trial and error and eventually leads to an optimized drug carrier. Unfortunately, due to the unique characteristics of each drug, the deduction of advanced general concepts remains challenging. Furthermore, the introduction of complex moieties or specifically modified polymers hampers systematic investigations regarding polymer-drug compatibility as well as clinical translation. In this study, we reduced the complexity to isolate the crucial factors determining drug loading. Therefore, the compatibility of 18 different amphiphilic polymers for five different hydrophobic drugs was determined empirically. Subsequently, the obtained specificities were compared to theoretical compatibilities derived from either the Flory-Huggins interaction parameters or the Hansen solubility parameters. In general, the Flory-Huggins interaction parameters were less suited to correctly estimate the experimental drug solubilization compared to the Hansen solubility parameters. The latter were able to correctly predict some trend regarding good and poor solubilizers, yet the overall predictive strength of Hansen solubility parameters is clearly unsatisfactory.

Single Crystal FLIM Characterization of Clofazimine Loaded in Silica-Based Mesoporous Materials and Zeolites.

Clofazimine (CLZ) is an effective antibiotic used against a wide spectrum of Gram-positive bacteria and leprosy. One of its main drawbacks is its poor solubility in water. Silica based materials are used as drug delivery carriers that can increase the solubility of different hydrophobic drugs. Here, we studied how the properties of the silica framework of the mesoporous materials SBA-15, MCM-41, Al-MCM-41, and zeolites NaX, NaY, and HY affect the loading, stability, and distribution of encapsulated CLZ. Time-correlated single-photon counting (TCSPC) and fluorescence lifetime imaging microscopy (FLIM) experiments show the presence of neutral and protonated CLZ (1.3-3.8 ns) and weakly interacting aggregates (0.4-0.9 ns), along with H- and J-type aggregates (<0.1 ns). For the mesoporous and HY zeolite composites, the relative contribution to the overall emission spectra from H-type aggregates is low (<10%), while for the J-type aggregates it becomes higher (~30%). For NaX and NaY the former increased whereas the latter decreased. Although the CLZ@mesoporous composites show higher loading compared to the CLZ@zeolites ones, the behavior of CLZ is not uniform and its dynamics are more heterogeneous across different single mesoporous particles. These results may have implication in the design of silica-based drug carriers for better loading and release mechanisms of hydrophobic drugs.

Drug targeted virtual screening and molecular dynamics of LipU protein of Mycobacterium tuberculosis and Mycobacterium leprae.

The lipolytic protein LipU was conserved in mycobacterium sp. including M. tuberculosis (MTB LipU) and M. leprae (MLP LipU). The MTB LipU was identified in extracellular fraction and was reported to be essential for the survival of mycobacterium. Therefore to address the problem of drug resistance in pathogen, LipU was selected as a drug target and the viability of finding out some FDA approved drugs as LipU inhibitors in both the cases was explored. Three-dimensional (3D) model structures of MTB LipU and MLP LipU were generated and stabilized through molecular dynamics (MD). FDA approved drugs were screened against these proteins. The result showed that the top-scoring compounds for MTB LipU were Diosmin, Acarbose and Ouabain with the Glide XP score of -12.8, -11.9 and -11.7 kcal/mol, respectively, whereas for MLP LipU protein, Digoxin (-9.2 kcal/mol), Indinavir (-8.2 kcal/mol) and Travoprost (-8.2 kcal/mol) showed highest affinity. These drugs remained bound in the active site pocket of MTB LipU and MLP LipU structure and interaction grew stronger after dynamics. RMSD, RMSF and Rg were found to be persistent throughout the simulation period. Hydrogen bonds along with large number of hydrophobic interactions stabilized the complex structures. Binding free energies obtained through Prime/MM-GBSA were found in the significant range from -63.85 kcal/mol to -34.57 kcal/mol for MTB LipU and -71.33 kcal/mol to -23.91 kcal/mol for MLP LipU. The report suggested high probability of these drugs to demolish the LipU activity and could be probable drug candidates to combat TB and leprosy disease.

Systematic modifications of amino acid-based organogelators for the investigation of structure-property correlations in drug delivery system.

Thermogels, used as multi-functional drug-loading materials, have properties that mainly rely on their gelator structure. Although a large variety of organogel systems are used as drug delivery carriers, relatively few have been investigated in terms of their structure-property correlations based on amino acid derivative gelators. Here, a series of amino acid based gelators were synthesized to explore the role of the gelator structure on functional properties, with the aim of establishing a connection between the molecular parameters and gel properties. By varying the three substitutions of the gelator backbone, it was found that a comprehensive interaction, consisting of hydrophobic forces, H-bonding interactions, conformational flexibility and steric repulsion, play a crucial role in determining the gelation properties. Hansen solubility parameters were employed to explore the solvent effect on the network forming and gel properties. From an analysis of the morphologies obtained from polarized optical microscope (POM), atomic force microscopic images (AFM) and scanning electron microscopy (SEM), the gelator structure was found to have an impact on the self-assembly. According to the X-ray diffraction (XRD), the possible conformations adopted by the gelators were revealed through molecular modelling. The ability to form intermolecular H-bonding is vital in molecular packing and, thus, gelation. A structure-property relationship was developed and proposed to provide a theoretical basis for controllable drug delivery implants.

Tunable Physical Properties of Ethylcellulose/Gelatin Composite Nanofibers by Electrospinning.

In this work, the ethylcellulose/gelatin blends at various weight ratios in water/ethanol/acetic acid solution were electrospun to fabricate nanofibers with tunable physical properties. The solution compatibility was predicted based on Hansen solubility parameters and evaluated by rheological measurements. The physical properties were characterized by scanning electron microscopy, porosity, differential scanning calorimetry, thermogravimetry, Fourier transform infrared spectroscopy, and water contact angle. Results showed that the entangled structures among ethylcellulose and gelatin chains through hydrogen bonds gave rise to a fine morphology of the composite fibers with improved thermal stability. The fibers with higher gelatin ratio (75%), possessed hydrophilic surface (water contact angle of 53.5°), and adequate water uptake ability (1234.14%), while the fibers with higher ethylcellulose proportion (75%) tended to be highly water stable with a hydrophobic surface (water contact angle of 129.7°). This work suggested that the composite ethylcellulose/gelatin nanofibers with tunable physical properties have potentials as materials for bioactive encapsulation, food packaging, and filtration applications.

Effect of XlogP and Hansen Solubility Parameters on Small Molecule Modified Paclitaxel Anticancer Drug Conjugates Self-Assembled into Nanoparticles.

Small molecule modified anticancer drug conjugates (SMMDCs) can self-assemble into nanoparticles (NPs) as therapeutic NP platforms for cancer treatment. Here we demonstrate that the XlogP and Hansen solubility parameters of paclitaxel (PTX) SMMDCs is essential for SMMDCs self-assembling into NPs. The amorphous state of PTX SMMDCs will also affect SMMDCs self-assembling into NPs. However, the antitumor activity of these PTX SMMDCs NPs decreased along with their XlogP values, indicating that a suitable XlogP value for designing the SMMDCs is important for self-assembling into NPs and for possessing antitumor activity. For higher level XlogP SMMDCs, a degradable linker should be considered in the design of SMMDCs to overcome the problem of lower antitumor activity. It is preferable that the hydrophilic groups in the SMMDCs should be present on the surface of self-assembling NPs.

Production of cocrystals in an excipient matrix by spray drying.

Spray drying is a well-established scale-up technique for the production of cocrystals. However, to the best of our knowledge, the effect of introducing a third component into the feed solution during the spray drying process has never been investigated. Cocrystal formation in the presence of a third component by a one-step spray drying process has the potential to reduce the number of unit operations which are required to produce a final pharmaceutical product (e.g. by eliminating blending with excipient). Sulfadimidine (SDM), a poorly water soluble active pharmaceutical ingredient (API), and 4-aminosalicylic acid (4ASA), a hydrophilic molecule, were used as model drug and coformer respectively to form cocrystals by spray drying in the presence of a third component (excipient). The solubility of the cocrystal in the excipient was measured using a thermal analysis approach. Trends in measured solubility were in agreement with those determined by calculated Hansen Solubility Parameter (HSP) values. The ratio of cocrystal components to excipient was altered and cocrystal formation at different weight ratios was assessed. Cocrystal integrity was preserved when the cocrystal components were immiscible with the excipient, based on the difference in Hansen Solubility Parameters (HSP). For immiscible systems (difference in HSP > 9.6 MPa0.5), cocrystal formation occurred even when the proportion of excipient was high (90% w/w). When the excipient was partly miscible with the cocrystal components, cocrystal formation was observed post spray drying, but crystalline API and coformer were also recovered in the processed powder. An amorphous dispersion was formed when the excipient was miscible with the cocrystal components even when the proportion of excipient used as low (10% w/w excipient). For selected spray dried cocrystal-excipient systems an improvement in tableting characteristics was observed, relative to equivalent physical mixtures.

Biophysical insights into the interaction of hen egg white lysozyme with therapeutic dye clofazimine: modulation of activity and SDS induced aggregation of model protein.

The present study details the binding process of clofazimine to hen egg white lysozyme (HEWL) using spectroscopy, dynamic light scattering, transmission electron microscopy (TEM), and molecular docking techniques. Clofazimine binds to the protein with binding constant (Kb) in the order of 1.57 × 104 at 298 K. Binding process is spontaneous and exothermic. Molecular docking results suggested the involvement of hydrogen bonding and hydrophobic interactions in the binding process. Bacterial cell lytic activity in the presence of clofazimine increased to more than 40% of the value obtained with HEWL only. Interaction of the drug with HEWL induced ordered secondary structure in the protein and molecular compaction. Clofazimine also effectively inhibited the sodium dodecyl sulfate (SDS) induced amyloid formation in HEWL and caused disaggregation of preformed fibrils, reinforcing the notion that there is involvement of hydrophobic interactions and hydrogen bonding in the binding process of clofazimine with HEWL and clofazimine destabilizes the mature fibrils. Further, TEM images confirmed that fibrillar species were absent in the samples where amyloid induction was performed in the presence of clofazimine. As clofazimine is a drug less explored for the inhibition of fibril formation of the proteins, this study reports the inhibition of SDS-induced amyloid formation of HEWL by clofazimine, which will help in the development of clofazimine-related molecules for the treatment of amyloidosis.

Polymer-water partition coefficients in polymeric passive samplers.

Passive samplers are of the most applied methods and tools for measuring concentration of hydrophobic organic compounds in water (c 1W ) in which the polymer-water partition coefficients (D) are of fundamental importance for reliability of measurements. Due to the cost and time associated with the experimental researches, development of a predictive method for estimation and evaluation of performance of polymeric passive samplers for various hydrophobic organic compounds is highly needed and valuable. For this purpose, in this work, following the fundamental chemical thermodynamic equations governing the concerned local equilibrium, successful attempts were made to establish a theoretical model of polymer-water partition coefficients. Flory-Huggins model based on the Hansen solubility parameters was used for calculation of activity coefficients. The method was examined for reliability of calculations using collected data of three polymeric passive samplers and ten compounds. A regression model of form ln(D) = 0.707ln(c 1p ) - 2.7391 with an R 2  = 0.9744 was obtained to relate the polymer-water partition coefficients (D) and concentration of hydrophobic organic compounds in passive sampler (c 1p ). It was also found that polymer-water partition coefficients are related to the concentration of hydrophobic organic compounds in water (c 1W ) as ln(D) = 2.412ln(c 1p ) - 9.348. Based on the results, the tie lines of concentration for hydrophobic organic compounds in passive sampler (c 1p ) and concentration of hydrophobic organic compounds in water (c 1W ) are in the form of ln(c 1W ) = 0.293ln(c 1p ) + 2.734. The composition of water sample and the interaction parameters of dissolved compound-water and dissolved compound-polymer, temperature, etc. actively influence the values of partition coefficient. The discrepancy observed over experimental data can be simply justified based on the local condition of sampling sites which alter these effective factors.

Exploring the effect of hydrophilic and hydrophobic structure of grafted polymeric micelles on drug loading.

The objective of this paper is to explore the effect of hydrophilic and hydrophobic structure of grafted polymeric micelles on drug loading, and elucidate whether drug-polymer compatibility, as predicted by Hansen solubility parameters (HSPs), can be used as a tool for drug-polymer pairs screening and guide the design of grafted polymeric micelles. HSPs of 27 drugs and three grafted copolymers were calculated according to group contribution method. The drug-polymer compatibilities were evaluated using the approaches of Flory-Huggins interaction parameters (χFH) and polarity difference (△Xp). Two models, model A and B, were put forward for drug-polymer compatibility prediction. In model A, hydrophilic/hydrophobic part as a whole was regarded as one segment. And, in model B, hydrophilic and hydrophobic segments were evaluated individually. First of all, using chitosan (CS)-grafted-glyceryl monooeate (GMO) based micelle as an example, the suitability of model A and model B for predicating drug-polymer compatibility was evaluated theoretically. Thereafter, corresponding experiments were carried out to check the validity of the theoretical prediction. It was demonstrated that Model B, which evaluates drug compatibility with both hydrophilic and hydrophobic segments of the copolymer, is more reliable for drug-polymer compatibility prediction. Moreover, the approach of model B allows for the selection of a defined grafted polymer with for a specific drug and vice versa. Thus, drug compatibility evaluation via HSPs with both hydrophilic and hydrophobic segments is a suitable tool for the rational design of grafted polymeric micelles. The molecular dynamics (MD) simulation study provided further support to the established model and experimental results.

Fractionation and analysis of mycobacterial proteins.

The extraction and isolation of native bacterial proteins continue to be valuable technical pursuits in order to understand bacterial physiology, screen for virulence determinants, and describe antigens. In this chapter, methods for the manipulation of whole mycobacterial cells are described in detail. Specifically, the concentration of spent culture filtrate media is described in order to permit separation of soluble, secreted proteins; several discrete separation techniques, including precipitation of protein mixtures with ammonium sulfate and separation of proteins by hydrophobic chromatography are also provided. Similarly, the generation of whole cell lysate and facile separation of lysate into subcellular fractions to afford cell wall, cell membrane, and cytosol enriched proteins is described. Due to the hydrophobic nature of cell wall and cell membrane proteins, several extraction protocols to resolve protein subsets (such as extraction with urea and SDS) are also provided, as well as a separation technique (isoelectric focusing) that can be applied to separate hydrophobic proteins. Lastly, two commonly used analytical techniques, in-gel digestion of proteins for LC-MS and analysis of intact proteins by MALDI-ToF MS, are provided for rapid analysis of discrete proteins within subcellular or chromatographic fractions. While these methods were optimized for the manipulation of Mycobacterium tuberculosis cells, they have been successfully applied to extract and isolate Mycobacterium leprae, Mycobacterium ulcerans, and Mycobacterium avium proteins. In addition, a number of these methods may be applied to extract and analyze mycobacterial proteins from cell lines and host derived samples.

Adhesion of the ulcerative pathogen Mycobacterium ulcerans to DACC-coated dressings.

OBJECTIVE: Mycobacterium ulcerans is the causative agent of Buruli ulcer disease, the third most common mycobacteriosis after tuberculosis and leprosy and an emerging public health threat in sub-Saharan Africa. The bacteria produce a diffusible cytotoxin called mycolactone, which triggers the formation of necrotic lesions in cutaneous and subcutaneous tissues. The principal aim of this study was to characterise the cell surface hydrophobicity of Mycobacterium ulcerans and determine if bacteria bind to dialkyl carbamoyl chloride (DACC)-coated dressings through hydrophobic interactions in vitro. Since mycolactone displays hydrophobic groups, a secondary aim was to compare mycolactone binding to hydrophobic and standard dressings. METHODS: We used hydrophobic interaction chromatography to evaluate the cell surface hydrophobicity of Mycobacterium ulcerans, compared to that of other microorganisms colonising wounds. The binding of Mycobacterium ulcerans bacteria to DACC-coated and control dressings was then assessed quantitatively by measurement of microbial adenosine triphosphate (ATP), while that of mycolactone was evaluated by fluorescence spectroscopy. RESULTS: Compared to Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa, Mycobacterium ulcerans displayed the highest cell surface hydrophobicity, irrespective of the bacterial production of mycolactone. Mycobacterium ulcerans bacteria bound to DACC-coated dressings [corrected] better than untreated controls. Mycolactone did not bind stably to hydrophobic, nor standard dressings, in the conditions tested. CONCLUSION: Retention of Mycobacterium ulcerans and other wound pathogens to DACC-coated dressings may help reduce the bacterial load in Buruli ulcers and thereby improve healing. Dressings efficiently capturing mycolactone may bring an additional clinical benefit, by accelerating the elimination of the toxin during the course of antibiotic treatment.

A simple thermodynamic approach to predict responses from polymer-coated quartz crystal microbalance sensors exposed to organic vapors.

As of lately, the demand for developing artificial sensors with improved capabilities for the detection of explosives, toxics or drugs has increased. Ideally, sensor devices should provide high sensitivity and give a response that is specific to a given target molecule without being influenced by possible interfering molecules in the atmosphere. These properties strongly depend on the structure of the chemical compound used as a sensitive material. It is thus crucial to select the right compound and this step would be facilitated with the aid of predictive tools. The present investigations have been focused on a family of functionalized polysiloxane polymers deposited on a QCM device, producing only weak interactions compatible with reversible sensors. The quartz frequency variation at equilibrium has been linked to the partition coefficient that was evaluated using a thermodynamic description of the adsorption process. We have shown that the relative responses of two polymers can be directly determined from the Gibbs free enthalpy of mixing as determined from NMR measurements performed on neat liquid mixtures. An equivalence of this term-including both enthalpy and entropy contributions-to the energy interaction term calculated using Hansen solubility coefficients, has been demonstrated previously. These results constitute a basis for the development of a numerical program for calculating equilibrium sensor responses. For small molecules, the adsorption kinetics can be easily accounted for by a Fick diffusion coefficient estimated from the Van der Waals volume.

Exopolysaccharides modify functional properties of whey protein concentrate.

The objective of this research was to produce whey protein concentrate (WPC) with modified functionality using exopolysaccharide- (EPS) producing cultures. Two different EPS-producing cultures, Lactococcus lactis ssp. cremoris JFR and Streptococcus thermophilus, producing EPS1 and EPS2 respectively, were used in this study. One EPS-nonproducing commercial cheese culture (DVS 850; Chr. Hansen, Milwaukee, WI) was used as the control. Reconstituted sweet whey powder was used in this study to eliminate variations from fresh whey. Cultures grown overnight in reconstituted WPC (10% wt/vol) were added, directly or after overnight cooling (cooled EPS), at 2% (wt/vol) to 6% (wt/wt) solution of reconstituted whey. Whey was then high-temperature, short-time pasteurized at 75 °C for 35s and ultrafiltered to a volume reduction factor of 5. Ultrafiltered whey (retentate) was spray dried at inlet and outlet air temperatures of 200 and 90 °C, respectively, to obtain WPC. In general, the solubility of WPC was higher at pH 7 than at pH 3. Whey protein concentrate containing EPS2 exhibited higher protein solubility than did WPC containing no EPS. Also, the presence of EPS in WPC decreased protein denaturation. The emulsifying ability of WPC containing EPS was higher than that in control. Addition of EPS to WPC significantly enhanced its gelling ability. Foam overrun and hydrophobicity of WPC were not affected by addition of EPS. In conclusion, data obtained from this study show that EPS modify WPC functionality. The extent of modification depends on the type of EPS. Cooling of culture containing EPS before its addition to whey further reduced WPC protein denaturation and increased its solubility at pH 7 and gel hardness.

Ciprofloxacin hydrochloride-loaded glyceryl monostearate nanoparticle: factorial design of Lutrol F68 and Phospholipon 90G.

PURPOSE: This investigation was undertaken to develop glyceryl monostearate (Geleol)-based solid lipid nanoparticles (SLNs) of a hydrophilic drug ciprofloxacin HCl. METHODS: Hansen's solubility parameter study was carried out in screening of a suitable carrier and solvent system. Subsequently, SLNs were prepared by solvent diffusion evaporation method and investigated for particle size, polydispersity index (PDI), zeta potential (ZP), entrapment efficiency (EE) and drug release behaviour. RESULTS: Variations in SLN composition resulted in particle sizes between 170 and 810 nm and ZPs between 8 and 14 mV. The maximum EE was found to be 26.3% with particle size of 188.8 nm. SLN can sustain the release of drug for up to 15 h and it shows Higuchi matrix model as the best-fitted model. SLNs were stable without aggregation of particles under storage conditions. CONCLUSIONS: The results of this study provide the framework for further study involving the SLN formulation for hydrophilic drug molecule.

Improvement of flow and bulk density of pharmaceutical powders using surface modification.

Improvement in flow and bulk density, the two most important properties that determine the ease with which pharmaceutical powders can be handled, stored and processed, is done through surface modification. A limited design of experiment was conducted to establish a standardized dry coating procedure that limits the extent of powder attrition, while providing the most consistent improvement in angle of repose (AOR). The magnetically assisted impaction coating (MAIC) was considered as a model dry-coater for pharmaceutical powders; ibuprofen, acetaminophen, and ascorbic acid. Dry coated drug powders were characterized by AOR, particle size as a function of dispersion pressure, particle size distribution, conditioned bulk density (CBD), Carr index (CI), flow function coefficient (FFC), cohesion coefficient using different instruments, including a shear cell in the Freeman FT4 powder rheometer, and Hansen flowability index. Substantial improvement was observed in all the measured properties after dry coating relative to the uncoated powders, such that each powder moved from a poorer to a better flow classification and showed improved dispersion. The material intrinsic property such as cohesion, plotted as a function of particle size, gave a trend similar to those of bulk flow properties, AOR and CI. Property improvement is also illustrated in a phase map of inverse cohesion (or FFC) as a function of bulk density, which also indicated a significant positive shift due to dry coating. It is hoped that such phase maps are useful in manufacturing decisions regarding the need for dry coating, which will allow moving from wet granulation to roller compaction or to direct compression based formulations.