Albumin is an important factor in the control of serum free fatty acid flux in both male and female mice.

Albumin knockout (Alb-/-) mice exhibit a low plasma free fatty acid (FFA) concentration, but it was not known if the suppressed concentration reflects a lower rate of appearance (Ra) of FFA in the circulation (i.e., lower FFA flux) or if the absence of albumin alters the relationship between FFA flux and concentration. For understanding the role of albumin in FFA transport through the bloodstream, it is not sufficient to rely on FFA concentration data alone. Therefore, we developed a method to study FFA kinetics in Alb-/- mice. Using an albumin-free formulation of [U-13C]palmitate tracer, serum FFA kinetics were tested in Alb-/- and wild-type (WT) mice. Results indicate that the flux of FFA in serum of Alb-/- mice was significantly lower than in WT mice (P < 0.05), while albumin deficiency did not alter the relationship between FFA flux and concentration. Next, to test if suppressed lipolysis might have also been involved in the suppressed FFA kinetics, gene expression of a lipolytic enzyme (adipose triglyceride lipase, Atgl) and a marker of lipolysis (phosphorylation of hormone-sensitive lipase, p-HSL) were measured in adipose tissue. In contrast to the low FFA flux in Alb-/-, both Atgl gene expression and p-HSL protein were significantly higher in adipose tissue of Alb-/- than in WT mice (P < 0.05). Thus, the low FFA flux in Alb-/- appeared to be driven by the absence of albumin's FFA binding functions rather than through regulation of lipolysis, indicating that albumin is an important factor in determining the flux of FFA in circulation.NEW & NOTEWORTHY To improve understanding of the albumin protein's function in vivo, we tested plasma free fatty acid kinetics in albumin knockout mice compared with wild-type mice. Using a new tracer formulation strategy, it was discovered that the appearance rate of free fatty acids in serum is lower in albumin knockout mice than in wild-type mice. The results indicate that albumin is a major controller of free fatty acid kinetics.

Tunable Drug Release Rate Using Modular Oral Dosage Forms.

Oral dosage forms with adjustable drug release profiles were prepared using progesterone (PGR) as a poorly-soluble model drug. The dosage forms were made as stack assemblies of functional modules. The modules were made as PGR-carrying HPMC films cut into wafer-like circular pieces. Two types of modules were used in the study; one exhibited comparatively fast drug release and the other slow release. The fast vs. slow release of each type of film utilized resulted from the grade of HPMC used in each case. Drug loading in the assembly was controlled through the total number of modules. By adjusting the proportions of the two types of modules, it is possible to fine-tune the drug release rate of the multi-layer assemblies to a wide range of profiles, bracketed between a high and low end, corresponding to the inherently fastest or slowest release obtainable with the specific materials and procedures employed. This procedure is suitable for adjusting the spring-and-parachute parameters for enhancing/optimizing the bioavailability of poorly-soluble drugs, and for developing patient-centric formulations.

Benzoic acid complexes with Eudragit E100®: New alternative antimicrobial preservatives.

Given that the use of some preservatives in cosmetics has been restricted, novel alternative preservatives are needed. The aim of this study was to characterize the physicochemical and antimicrobial properties of two polyelectrolyte complexes (EuB100 and EuB75Cl25), which were developed through hot melt extrusion (HME) using benzoic acid (BA) and Eudragit E100. Based on phase diagrams and an experimental statistical design, the solubility of the acid in the polymer and the HME conditions were established. Intermolecular interactions were evaluated through Fourier-transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), and X-ray powder diffraction (XRPD). Release behavior was determined for the systems. Antibacterial activity and ζ-potential were determined on Escherichia coli. FTIR revealed acid-base interaction, and XPS showed that the percentages of protonated nitrogen N1s were 13.5% for EuB100 and 20.3% for EuB75Cl25. The BA released showed a non-Fickian behavior, and a satisfactory antibacterial activity against E. coli was demonstrated at pH 6.9. The complexes modified ζ-potential, destabilizing the membrane functionality of E. coli. These complexes are potential antimicrobial preservatives with a greater spectrum of action, with bactericidal activity against E. coli in a wider pH range than uncomplexed BA, even at pH 6.9.

Modular solid dosage form design - Application to pH-independent release of a weak-base API.

A novel approach to solid dosage form design is investigated, whereby instead of blending the ingredients and subsequently compacting the mixture, the dosage form is made by assembling prefabricated components, each with a specific function. The approach was used to formulate a weak-base API (active pharmaceutical ingredient), such that the modular dosage forms exhibited pH-independent drug release. Tablet-like dosage forms of ciprofloxacin (CPR), used as model weak-base drug, were prepared in order to generate dosage forms exhibiting pH-independent drug release. The dosage forms were made by assembling two types of prefabricated modules onto 3D stacks. The modules were hydroxypropyl methylcellulose circular film wafers, loaded with either CPR or citric acid (CA). CA-wafers served the function of pH-modifier modules in the microenvironment of the dosage form during the dissolution process. In vitro drug release from dosage forms consisting of CA- and CPR-wafers stacked in alternate sequence was compared with the release from assemblies containing CPR-wafers only, under pH = 1.2 and pH = 6.8 conditions. In the absence of CA-wafers, CPR release was ~25-fold slower at pH = 6.8 compared to pH = 1.2. Inclusion of CA-wafers in the dosage form assembly accelerated and decelerated drug release at pH = 6.8 and pH = 1.2, respectively, which resulted in overlapping drug release profiles under the two pH conditions. The two drug release profiles met the criteria for sameness as assessed by the f1 (difference) and f2 (similarity) factors. Modeling of drug release kinetics pointed toward polymer erosion as the primary mechanism of drug release for the overlapping pH = 1.2 and pH = 6.8 profiles. In terms of their drug release properties, the multi-modular dosage form assemblies exhibited the attributes and behavior of single bodies, rather than the combined contributions from multiple individually-operating modules. The initial geometry of the dosage form, characterized by the surface area (SA), volume (V) and SA/V ratio accounted for drug release kinetics in the same fashion as for traditional tablet compacts.

Development of an antibacterial and anti-metalloproteinase dental adhesive for long-lasting resin composite restorations.

Despite all the advances in adhesive dentistry, dental bonds are still fragile due to degradation events that start during application of adhesive agents and the inherent hydrolysis of resin-dentin bonds. Here, we combined two outstanding processing methods (electrospinning and cryomilling) to obtain bioactive (antimicrobial and anti-metalloproteinase) fiber-based fillers containing a potent matrix metalloproteinase (MMP) inhibitor (doxycycline, DOX). Poly(ε)caprolactone solutions containing different DOX amounts (0, 5, 25, and 50 wt%) were processed via electrospinning, resulting in non-toxic submicron fibers with antimicrobial activity against Streptococcus mutans and Lactobacillus. The fibers were embedded in a resin blend, light-cured, and cryomilled for the preparation of fiber-containing fillers, which were investigated with antibacterial and in situ gelatin zymography analyzes. The fillers containing 0, 25, and 50 wt% DOX-releasing fibers were added to aliquots of a two-step, etch-and-rinse dental adhesive system. Mechanical strength, hardness, degree of conversion (DC), water sorption and solubility, bond strength to dentin, and nanoleakage analyses were performed to characterize the physico-mechanical, biological, and bonding properties of the modified adhesives. Statistical analyses (ANOVA; Kruskal-Wallis) were used when appropriate to analyze the data (α = 0.05). DOX-releasing fibers were successfully obtained, showing proper morphological architecture, cytocompatibility, drug release ability, slow degradation profile, and antibacterial activity. Reduced metalloproteinases (MMP-2 and MMP-9) activity was observed only for the DOX-containing fillers, which have also demonstrated antibacterial properties against tested bacteria. Adhesive resins modified with DOX-containing fillers demonstrated greater DC and similar mechanical properties as compared to the fiber-free adhesive (unfilled control). Concerning bonding performance to dentin, the experimental adhesives showed similar immediate bond strengths to the control. After 12 months of water storage, the fiber-modified adhesives (except the group consisting of 50 wt% DOX-loaded fillers) demonstrated stable bonds to dentin. Nanoleakage was similar among all groups investigated. DOX-releasing fibers showed promising application in developing novel dentin adhesives with potential therapeutic properties and MMP inhibition ability; antibacterial activity against relevant oral pathogens, without jeopardizing the physico-mechanical characteristics; and bonding performance of the adhesive.

Molecular and physical characterization of octenyl succinic anhydride-modified starches with potential applications in pharmaceutics.

Five commercially available starches modified with octenyl succinic anhydride (OSA) are characterized at a molecular, physicochemical and bulk level providing useful data for designing pharmaceutical products. The degree of substitution (DS) of the starches range from 0.017 to 0.032 and their molecular weights (Mw) and radius of gyration (Rz) are lower than those of native starch, suggesting additional modification processes besides the chemical treatment with OSA. The ability of the starches to reduce the water surface tension keeps a direct relationship with the DS and an inverse association with the Mw. Thermal properties, crystallinity assays and morphology evidence that most modified starches characterize by amorphous aggregated structures, possibly generated by gelatinization processes, which favor the flow properties of the powders. Water sorption and surface energy behaviors seem to be related to the number of octenyl succinate (OS) moieties. After dispersion in water, shear-thinning and Newtonian behaviors also depend on the type of OS-starch.

Drug Solubilization by Means of Partition/Association Equilibrium Using a Modified Nanosized Dendrimeric Biopolymer.

The objective of this study is to elucidate the combined effects of a novel type of material being investigated as a new excipient, an octenylsuccinate-modified dendrimer-like biopolymer (OS-DLB) and poloxamer (PLX), on the solubility of poorly water-soluble compounds. Phenytoin (PHT), griseofulvin (GSF), ibuprofen (IBU), and loratadine (LOR) were used as model compounds. Phase solubility measurements were conducted to determine the relative proportions of API, OS-DLB, and PLX that result in the most stable dendrimeric complexes. The solubilizing power of OS-DLB increases with increasing hydrophobicity of the solute. In the presence of PLX, the solubilization effect of OS-DLB is modestly accentuated for the most hydrophobic drugs (IBU and LOR) but has no effect on the least hydrophobic one (PHT). The maximum potentiation effect of PLX on the solubilizing properties of OS-DLB was observed for GSF, the drug of intermediate hydrophobicity. Three different types of solubilization profiles were obtained in the study. All three different profiles can be appropriately described by a single solubilization model, depending on the specific parameter values. The defining parameters of the model reflect the hydrophobicity of the drug on the one hand and, on the other hand, the inherent tendency of the drug (crystal lattice energy) toward crystallization.

Azopolymer based nanoparticles for phototriggered drug delivery.

Controlled release by stimulus-responsive nanoparticles is oriented to increase the specificity of drug delivery, to improve the therapy effectiveness and minimizing side effects. This work presents the synthesis of photosensitive-polymeric nanoparticles as a potential system for localized drug delivery. First, the photoisomerizable amphiphilic-copolymer poly2-[4-phenylazophenoxy]ethyl acrylate-co-acrylic acid (PPAPE), was synthesized. Then, PPAPE was employed to prepare micellar nanoparticles by the nanoprecipitation method. Characterizations of the polymer were performed by proton nuclear magnetic resonance, X-ray photoelectron spectroscopy and FTIR spectroscopy. The morphology of the nanoparticles was analyzed by dynamic light scattering and transmission electron microscopy. Also, photostimulation response was confirmed by UV-VIS spectroscopy. Results indicate that the obtained photoresponsive nanoparticles have the size and photoisomerization necessary to perform the specific release of drugs.

Drug Solubilization by Means of a Surface-Modified Edible Biopolymer Enabled by Hot Melt Extrusion.

A coprocessing/formulation approach for increasing the solubility of poorly soluble drugs using solid dispersions is presented, whereby the active pharmaceutical ingredients (API) retains its crystalline state. The approach uses a biopolymer naturally produced as dendrimeric nanoparticles that has been surface-modified to act as a solubilizing agent. The solubilizing agent is enabled by hot melt extrusion to produce the solid dispersions. Four APIs, phenytoin (PHT), griseofulvin, ibuprofen, and loratadine were used as model compounds to evaluate solubility enhancement. The rank order in solubility enhancement follows that of the hydrophobicity of the APIs. The APIs remained predominantly crystalline after hot melt extrusion processing. However, APIs with weak crystal structure (ibuprofen and loratadine) underwent measurable crystallinity loss. The solubilizing power of the modified biopolymer increases with increasing hydrophobicity and strength of the crystal structure. The solubility is described in terms of a parallel liquid-phase partition-association. For one API (PHT), solubility enhancement was minimal. The dissimilar behavior of PHT is discussed in terms of the polarity match between the API and the hydrophobic microenvironment in the solubilizing agent. This approach is expected to apply to a large number of poorly soluble drugs, offering a complementary approach to existing processing and formulation drug solubilization methods.

Acid-base interactions in amorphous solid dispersions of lumefantrine prepared by spray-drying and hot-melt extrusion using X-ray photoelectron spectroscopy.

This study investigates drug-excipient interactions in amorphous solid dispersions (ASDs) of the model basic compound lumefantrine (LMN), with five acidic polymers. X-ray photoelectron spectroscopy (XPS) was used to measure the extent of the protonation of the tertiary amine in LMN by the five acidic polymers. The extent/efficiency of protonation of the ASDs was assessed a function of polymer type, manufacturing process (hot-melt extrusion vs. spray drying), and drug loading (DL). The most strongly acidic polymer, polystyrene sulfonic acid (PSSA) was found to be the most efficient polymer in protonating LMN, independently of manufacturing method and DL. The rank order for the protonation extent of LMN by each polymer is roughtly the same for both manufacturing processes. However, protonation efficiency of polymers of similar acidic strength ranged from ∼0% to 75% (HPMCAS and Eudragit L100-55, respectively), suggesting an important role of molecular/mixing effects. For some polymers, including Eudragit L100 55 and HPMCP, spray-drying resulted in higher protonation efficiency compared to hot-melt extrusion. This result is attributable to a more favorable encounter between acid and base groups, when exposed to each other in solution phase. Increasing DL led to decreased protonation efficiency in most cases, particularly for polyacrylic acid, despite having the highest content of acidic groups per unit mass. These results indicate that the combined effects of acid strength and mixing phenomena regulate the efficiency of acid-base interactions in the ASDs.

Stain removal effect of novel papain- and bromelain-containing gels applied to enamel.

OBJECTIVES: The aims of the study are to prepare novel stain removal gel-based formulations containing papain or bromelain and to investigate their stain removal effect when applied to enamel. MATERIALS AND METHODS: Experimental bromelain- and papain-based stain removal gels were prepared. Next, enamel/dentin tooth samples (6 × 6 mm2, 4 mm in thickness) were obtained from bovine teeth, stained in coffee solution for 1 week, and measured with a digital spectrophotometer (Easyshade, Vita Zahnfabrik) for color assessment (baseline). The samples were then randomly allocated into four groups (n = 7), according to the stain removal agent applied: ContrastPM+ (Discus Dental, LLC), which is based on 20 wt.% carbamide peroxide (positive control); bromelain-based; papain-based; and no agent (negative control). The materials were applied once a week, three times per day, during 4 weeks, and following the directions of use from positive control. The samples were measured again with the Easyshade and using the CIEL * a * b * color system. The color change (ΔE *) results were obtained by subtracting the baseline values from the final color values obtained at each time point. The data were statistically analyzed using two-way repeated-measures analysis of variance and Student Newman Keuls's test as a post hoc test (α = 5 %). RESULTS: All stain removal agents produced greater color change than the negative control (p < .001), with the positive control demonstrating greater ΔE * values when compared to the experimental gels (p ≤ .004). The second application of all gels resulted in greater ΔE * values compared to the first application (p ≤ .025), although no color change was observed after the third application (p ≥ .051), regardless of the material evaluated. CLINICAL SIGNIFICANCE: The proposed gels containing proteolytic enzymes (bromelain or papain) of vegetal origin may hold significant clinical potential as active agents for the preparation of stain removal agents free of hydrogen/carbamide peroxide.

A dimensionless variable for the scale up and transfer of a roller compaction formulation.

Roller compaction is the most commonly employed dry granulation process in the pharmaceutical industry. While this process is increasingly used as an alternative to wet granulation, there are no parameter sets or system of equations to quickly scale up or transfer a formulation between two pieces of equipment. In this work, dimensionless variable was examined as a method to transfer the operating parameters of a formulation between two different pieces of equipment. This work was completed to establish the ground work for the development of a dimensionless relationship relating the operating parameters of the equipment to the porosity of the ribbon. The working hypothesis was three-fold, namely (i) that ribbons of the same porosity made with different equipment will have similar properties, (ii) that it is possible to establish an objective relationship between ribbon porosity and a combination of operating parameters and raw material attributes and (iii) that by expressing such parameter combination as a dimensionless variable, it will be possible to use the same relationship for different pieces of roller compaction equipment. The dimensionless variable RP/RS*HFS*True Density*D2 was found to correlate well with the ribbon porosity for the formulations and equipment used in these experiments. Depending on the formulation, the average difference in ribbon porosity between the two units varied between 0.012 and 0.024.

Investigation of Film with ß-Galactosidase Designed for Stabilization and Handling in Dry Configuration.

Gelatin-based films with an immobilized enzyme designed for extending the stability of the protein in dry, non-powder configuration with precise dosing attributes were subjected to stress conditions of temperature and relative humidity. ß-galactosidase was used as model functional protein. The film configuration preserved the activity of the enzyme under the different storage conditions investigated, which include room temperature under low (ambient) and high (75%) relative humidity, and 36 °C under low (oven) and high relative humidity conditions for a period of 46 days. The influence of the enzyme and plasticizer (glycerol) on the physical and mechanical properties of the films was investigated using DMA (dynamic mechanical analysis). Films containing 5% ß-galactosisdase and glycerol concentrations of 14% or greater exhibited greater tensile strength, Young's modulus, and elongation at break than films with equal concentrations of plasticizer but devoid of any enzyme. The surface texture of the films was analyzed using scanning electron microscopy (SEM). ß-galactosidase and glycerol have opposite effects on the surface morphology of the films. Increasing concentrations of the enzyme result in rougher film surface, whereas increasing the concentration of glycerol leads to films with denser and smoother surface. The results obtained suggest that the dry film configuration approach can help in facilitating the stabilization, handling, storage, and transportation of functional proteins in a cost effective manner.

Cosolvency approach for assessing the solubility of drugs in poly(vinylpyrrolidone).

The log-linear cosolvency model was applied for estimating the solubility of four drugs: ritonavir, griseofulvin, itraconazole and ketoconazole in poly(vinylpyrrolidone) (PVP). Cosolvent mixtures consisted of PVP mixed in different proportions with N-ethylpyrrolidone, which served as the monomeric analogue of the repeating unit of the polymer. Solubility in the monomer-polymer mixtures was determined by HPLC. As the configuration of the solvating unit in the solvent mixture changed from entirely monomeric to increasingly polymeric, the solubility of the drugs decreased in a fashion that follows the log-linear cosolvency model. The linear relationship was used to obtain estimates for the solubility of the drugs in the different grades of PVP. The solubility of the drugs in PVP is low (from <1% to ∼15% w/w). Among the set of drug solutes, ritonavir exhibited the highest solubility in PVP (w/w). Mixing with the monomer is most favorable for griseofulvin among the four drugs. However, the detrimental effect of polymerization on its solubility is more pronounced than for ritonavir. The mixing of itraconazole with the monomer is more favorable than the mixing of ketoconazole. However, despite the molecular similarity between ketaconazole and itraconazole, the solubility of the latter is particularly affected by the polymeric configuration of the solvating unit, to the point of exhibiting differences in solubility resulting from the chain length of the grade of PVP used. The log-linear cosolvency model is a useful tool for estimating the solubility of the drugs in the polymer at room temperature, while providing quantitative information on the differences in mixing behavior of the four model compounds.

A Smart Capsule With GI-Tract-Location-Specific Payload Release.

In this paper, we present a smart capsule for location-specific drug release in the gastrointestinal tract. Once activated through a magnetic proximity fuse, the capsule opens up and releases its powdered payload in a location specified by an implanted miniature magnetic marker or an externally worn larger magnet. The capsule (9 mm × 26 mm) comprises of two compartments: one contains a charged capacitor and a reed switch, while the second one houses the drug reservoir capped by a taut nylon thread intertwined with a nichrome wire. The nichrome wire is connected to the capacitor through the reed switch. The capacitor is charged to 2.7 V before ingestion and once within the proximity of the permanent magnet; the reed switch closes, discharging the capacitor through the nichrome wire, melting the nylon thread, detaching the cap, and emptying the drug reservoir.

The influence of API concentration on the roller compaction process: modeling and prediction of the post compacted ribbon, granule and tablet properties using multivariate data analysis.

OBJECTIVE: While previous research has demonstrated roller compaction operating parameters strongly influence the properties of the final product, a greater emphasis might be placed on the raw material attributes of the formulation. There were two main objectives to this study. First, to assess the effects of different process variables on the properties of the obtained ribbons and downstream granules produced from the rolled compacted ribbons. Second, was to establish if models obtained with formulations of one active pharmaceutical ingredient (API) could predict the properties of similar formulations in terms of the excipients used, but with a different API. MATERIALS AND METHODS: Tolmetin and acetaminophen, chosen for their different compaction properties, were roller compacted on Fitzpatrick roller compactor using the same formulation. Models created using tolmetin and tested using acetaminophen. The physical properties of the blends, ribbon, granule and tablet were characterized. Multivariate analysis using partial least squares was used to analyze all data. RESULTS: Multivariate models showed that the operating parameters and raw material attributes were essential in the prediction of ribbon porosity and post-milled particle size. The post compacted ribbon and granule attributes also significantly contributed to the prediction of the tablet tensile strength. CONCLUSIONS: Models derived using tolmetin could reasonably predict the ribbon porosity of a second API. After further processing, the post-milled ribbon and granules properties, rather than the physical attributes of the formulation were needed to predict downstream tablet properties. An understanding of the percolation threshold of the formulation significantly improved the predictive ability of the models.

Physicomechanical and antibacterial properties of experimental resin-based dental sealants modified with nylon-6 and chitosan nanofibers.

This study aimed to develop and evaluate resin-based experimental dental sealants containing electrospun nylon-6 (N6) and chitosan (CH) fibers in an attempt to improve the physicomechanical properties and provide an antibacterial protective effect, respectively. Electrospun N6 and CH mats were immersed into a resin mixture, light-cured, and then cryomilled to obtain micron-sized resin-modified fiber particles. Different levels of the novel cryomilled particles (i.e. 1, 2.5, and 5% relative to the resin mixture, % by weight) were used to prepare the N6- and CH-containing sealants. A commercial sealant and the experimental resin mixture (unfilled) were used as controls. Flexural strength (FS), Vickers microhardness (VH), and agar diffusion tests were performed. The data were analyzed at the 5% significance level. No significant difference in fiber diameter of N6 (503 ± 31 nm) and CH (595 ± 38 nm) was observed. Upon cryomilling, the resin-modified CH and N6 mats led to the formation of irregularly-shaped particles, with an average diameter of 14.24 µm and 15.87 µm, respectively. CH-5% had significantly higher FS (115.3 ± 1.3 MPa) than all the other groups. CH-1% had significantly higher hardness values (38.3 ± 0.3 VHN) than all the other groups. Collectively, the results indicated that CH-containing sealants presented the highest FS and hardness; however, none of the CH-containing sealants displayed antimicrobial properties.

Matrix-assisted cocrystallization (MAC) simultaneous production and formulation of pharmaceutical cocrystals by hot-melt extrusion.

A novel method for the simultaneous production and formulation of pharmaceutical cocrystals, matrix-assisted cocrystallization (MAC), is presented. Hot-melt extrusion (HME) is used to create cocrystals by coprocessing the drug and coformer in the presence of a matrix material. Carbamazepine (CBZ), nicotinamide (NCT), and Soluplus were used as a model drug, coformer, and matrix, respectively. The MAC product containing 80:20 (w/w) cocrystal:matrix was characterized by differential scanning calorimetry, Fourier transform infrared spectroscopy, and powder X-ray diffraction. A partial least squares (PLS) regression model was developed for quantifying the efficiency of cocrystal formation. The MAC product was estimated to be 78% (w/w) cocrystal (theoretical 80%), with approximately 0.3% mixture of free (unreacted) CBZ and NCT, and 21.6% Soluplus (theoretical 20%) with the PLS model. A physical mixture (PM) of a reference cocrystal (RCC), prepared by precipitation from solution, and Soluplus resulted in faster dissolution relative to the pure RCC. However, the MAC product with the exact same composition resulted in considerably faster dissolution and higher maximum concentration (∼five-fold) than those of the PM. The MAC product consists of high-quality cocrystals embedded in a matrix. The processing aspect of MAC plays a major role on the faster dissolution observed. The MAC approach offers a scalable process, suitable for the continuous manufacturing and formulation of pharmaceutical cocrystals.

A novel method for determining the solubility of small molecules in aqueous media and polymer solvent systems using solution calorimetry.

PURPOSE: To explore the application of solution calorimetry for measuring drug solubility in experimentally challenging situations while providing additional information on the physical properties of the solute material. METHODS: A semi-adiabatic solution calorimeter was used to measure the heat of dissolution of prednisolone and chlorpropamide in aqueous solvents and of griseofulvin and ritonavir in viscous solutions containing polyvinylpyrrolidone and N-ethylpyrrolidone. RESULTS: Dissolution end point was clearly ascertained when heat generation stopped. The heat of solution was a linear function of dissolved mass for all drugs (<10% RSD, except for chlorpropamide). Heats of solution of 9.8 ± 0.8, 28.8 ± 0.6, 45.7 ± 1.6 and 159.8 ± 20.1 J/g were obtained for griseofulvin, ritonavir, prednisolone and chlorpropamide, respectively. Saturation was identifiable by a plateau in the heat signal and the crossing of the two linear segments corresponds to the solubility limit. The solubilities of prednisolone and chlopropamide in water by the calorimetric method were 0.23 and 0.158 mg/mL, respectively, in agreement with the shake-flask/HPLC-UV determined values of 0.212 ± 0.013 and 0.169 ± 0.015 mg/mL, respectively. For the higher solubility and high viscosity systems of griseofulvin and ritonavir in NEP/PVP mixtures, respectively, solubility values of 65 and 594 mg/g, respectively, were obtained. CONCLUSION: Solution calorimetry offers a reliable method for measuring drug solubility in organic and aqueous solvents. The approach is complementary to the traditional shake-flask method, providing information on the solid properties of the solute. For highly viscous solutions, the calorimetric approach is advantageous.