Determination of the drug solubility at the melt temperature in silicone intravaginal rings using dynamic mechanical analysis

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High speed DSC (hyper-DSC) as a tool to measure the solubility of a drug within a solid or semi-solid matrix

Conventional differential scanning calorimetry (DSC) techniques are commonly used to quantify the solubility of drugs within polymeric-controlled delivery systems. However, the nature of the DSC experiment, and in particular the relatively slow heating rates employed, limit its use to the measurement of drug solubility at the drug's melting temperature. Here, we describe the application of hyper-DSC (HDSC), a variant of DSC involving extremely rapid heating rates, to the calculation of the solubility of a model drug, metronidazole, in silicone elastomer, and demonstrate that the faster heating rates permit the solubility to be calculated under non-equilibrium conditions such that the solubility better approximates that at the temperature of use. At a heating rate of 400 degrees C/min (HDSC), metronidazole solubility was calculated to be 2.16 mg/g compared with 6.16 mg/g at 20 degrees C/min. (C) 2005 Elsevier B.V. All rights reserved.

High speed DSC (hyper-DSC) as a tool to measure the solubility of a drug within a solid or semi-solid matrix

Conventional differential scanning calorimetry (DSC) techniques are commonly used to quantify the solubility of drugs within polymeric-controlled delivery systems. However, the nature of the DSC experiment, and in particular the relatively slow heating rates employed, limit its use to the measurement of drug solubility at the drug's melting temperature. Here, we describe the application of hyper-DSC (HDSC), a variant of DSC involving extremely rapid heating rates, to the calculation of the solubility of a model drug, metronidazole, in silicone elastomer, and demonstrate that the faster heating rates permit the solubility to be calculated under non-equilibrium conditions such that the solubility better approximates that at the temperature of use. At a heating rate of 400°C/min (HDSC), metronidazole solubility was calculated to be 2.16 mg/g compared with 6.16 mg/g at 20°C/min. © 2005 Elsevier B.V. All rights reserved.

Use of amino acids as counterions improves the solubility of the BCS II model drug, indomethacin

The number of new chemical entities (NCE) is increasing every day after the introduction of combinatorial chemistry and high throughput screening to the drug discovery cycle. One third of these new compounds have aqueous solubility less than 20µg/mL [1]. Therefore, a great deal of interest has been forwarded to the salt formation technique to overcome solubility limitations. This study aims to improve the drug solubility of a Biopharmaceutical Classification System class II (BCS II) model drug (Indomethacin; IND) using basic amino acids (L-arginine, L-lysine and L-histidine) as counterions. Three new salts were prepared using freeze drying method and characterised by FT-IR spectroscopy, proton nuclear magnetic resonance ((1)HNMR), Differential Scanning Calorimetry (DSC) and Thermogravimetric analysis (TGA). The effect of pH on IND solubility was also investigated using pH-solubility profile. Both arginine and lysine formed novel salts with IND, while histidine failed to dissociate the free acid and in turn no salt was formed. Arginine and lysine increased IND solubility by 10,000 and 2296 fold, respectively. An increase in dissolution rate was also observed for the novel salts. Since these new salts have improved IND solubility to that similar to BCS class I drugs, IND salts could be considered for possible waivers of bioequivalence.

Characterisation of the Thermal, Spectroscopic and Drug Dissolution Properties of Mefenamic Acid and Polyoxyethylene–Polyoxypropylene Solid Dispersions

The aim of this study was to investigate the solubility of mefenamic acid (MA), a highly cohesive, poorly water-soluble drug in a copolymer of polyoxyethylene–polyoxypropylene (Lutrol F681), and to understand the effect drug polymer solubility has on in vitro dissolution of MA. Solid dispersions (SD) of MA were prepared by a hot melt method, using Lutrol F681 as a thermoplastic polymeric platform. High-speed differential scanning calorimetry (Hyper-DSC), Raman spectroscopy, powder X-ray diffractometry (PXRD) and hot-stage/?uorescence microscopy were used to assess the solubility of the drug in molten and solid polymer. Drug dissolution studies were subsequently conducted on single-phase solid solutions and biphasic SD using phosphate buffer pH 6.8 as dissolution media. Solubility investigations using Hyper-DSC, Raman spectroscopy and hot-stage microscopy suggested MA was soluble in molten Lutrol F681 up to a concentration of 35% (w/w). Conversely, the solubility in the solidstate matrix was limited to<15% (w/w); determined by Raman spectroscopy, PXRD and ?uorescence microscopy. As expected the dissolution properties of MA were signi?cantly in?uenced by the solubility of the drug in the polymer matrix. At a concentration of 10% (w/w) MA (a single phase solid solution) dissolution of MA in phosphate buffer 6.8 was rapid, whereas at a concentration of 50% (w/w) MA (biphasic SD) dissolution was signi?cantly slower. This study has clearly demonstrated the complexity of drug– polymer binary blends and in particular de?ning the solubility of a drug within a polymeric platform. Moreover, this investigation has demonstrated the signi?cant effect drug solubility within a polymeric matrix has upon the in vitro dissolution properties of solid polymer/drug binary blends.

Construction of Drug–Polymer Thermodynamic Phase Diagrams Using Flory–Huggins Interaction Theory: Identifying the Relevance of Temperature and Drug Weight Fraction to Phase Separation within Solid Dispersions

Amorphous drug-polymer solid dispersions have the potential to enhance the dissolution performance and thus bioavailability of BCS class II drug compounds. The principle drawback of this approach is the limited physical stability of amorphous drug within the dispersion. Accurate determination of the solubility and miscibility of drug in the polymer matrix is the key to the successful design and development of such systems. In this paper, we propose a novel method, based on Flory-Huggins theory, to predict and compare the solubility and miscibility of drug in polymeric systems. The systems chosen for this study are (1) hydroxypropyl methylcellulose acetate succinate HF grade (HPMCAS-HF)-felodipine (FD) and (2) Soluplus (a graft copolymer of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol)-FD. Samples containing different drug compositions were mixed, ball milled, and then analyzed by differential scanning calorimetry (DSC). The value of the drug-polymer interaction parameter ? was calculated from the crystalline drug melting depression data and extrapolated to lower temperatures. The interaction parameter ? was also calculated at 25 °C for both systems using the van Krevelen solubility parameter method. The rank order of interaction parameters of the two systems obtained at this temperature was comparable. Diagrams of drug-polymer temperature-composition and free energy of mixing (?G mix) were constructed for both systems. The maximum crystalline drug solubility and amorphous drug miscibility may be predicted based on the phase diagrams. Hyper-DSC was used to assess the validity of constructed phase diagrams by annealing solid dispersions at specific drug loadings. Three different samples for each polymer were selected to represent different regions within the phase diagram

Optimising drug solubilisation in amorphous polymer dispersions: rational selection of hot-melt extrusion processing parameters

The aim of this article was to construct a T–ϕ phase diagram for a model drug (FD) and amorphous polymer (Eudragit® EPO) and to use this information to understand the impact of how temperature–composition coordinates influenced the final properties of the extrudate. Defining process boundaries and understanding drug solubility in polymeric carriers is of utmost importance and will help in the successful manufacture of new delivery platforms for BCS class II drugs. Physically mixed felodipine (FD)–Eudragit® EPO (EPO) binary mixtures with pre-determined weight fractions were analysed using DSC to measure the endset of melting and glass transition temperature. Extrudates of 10 wt% FD–EPO were processed using temperatures (110°C, 126°C, 140°C and 150°C) selected from the temperature–composition (T–ϕ) phase diagrams and processing screw speed of 20, 100 and 200rpm. Extrudates were characterised using powder X-ray diffraction (PXRD), optical, polarised light and Raman microscopy. To ensure formation of a binary amorphous drug dispersion (ADD) at a specific composition, HME processing temperatures should at least be equal to, or exceed, the corresponding temperature value on the liquid–solid curve in a F–H T–ϕ phase diagram. If extruded between the spinodal and liquid–solid curve, the lack of thermodynamic forces to attain complete drug amorphisation may be compensated for through the use of an increased screw speed. Constructing F–H T–ϕ phase diagrams are valuable not only in the understanding drug–polymer miscibility behaviour but also in rationalising the selection of important processing parameters for HME to ensure miscibility of drug and polymer.

The Use of High Surface Area Silica and Supercritical Carbon Dioxide to Enhance Solubility of Poorly Water-Soluble Drugs

Purpose Poor water-solubility of BCS class II drugs can limit their commercialization because of reduced oral bioavailability. It has been reported that loading of drug by adsorption onto porous silica would enhance drug solubility due to the increased surface area available for solvent diffusion. In this work, solid dispersions are formed using supercritical carbon dioxide (scCO2). The aim of this research was to characterise the solid-state properties of scCO2 dispersion and to investigate the impact of altering scCO2 processing conditions on final amorphous product performance that could lead to enhancement of drug dissolution rate for BCS class II drugs. Methods Indomethacin (IND) was purchased from Sigma-Aldrich (Dorset, UK) and was used as a model drug with two grades of high surface area silica (average particle sizes 3&[micro] and 7&[micro]), which were obtained directly from Grace-Davison (Germany). Material crystallinity was evaluated using powder X-ray diffraction (PXRD, Rigaku™, miniflex II, Japan) and high-speed differential scanning calorimetry (Hyper-DSC 8000, Perkin Elmer, USA). Materials were placed in a high-pressure vessel consisting of a CO2 cylinder, a Thar™ Technologies P50 high-pressure pump and a 750 ml high-pressure vessel (Thar, USA). Physical mixtures were exposed to CO2 gas above its critical conditions. SEM imaging and elemental analysis were conducted using a Jeol 6500 FEGSEM (Advanced MicroBeam Inc., Austria). Drug release was examined using USP type II dissolution tester (Caleva™, UK). Results The two grades of silica were found to be amorphous using PXRD and Hyper-DSC. Using PXRD, it was shown that an increase in incubation time and pressure resulted in a decrease in the crystalline content. Drug release profiles from the two different silica formulations prepared under the same conditions are shown in Figure 1. It was found that there was a significant enhancement in drug release, which was influenced, by silica type and other experiment conditions such as temperature, pressure and exposure time. SEM imaging and elemental analysis showed drug deposited inside silica pores as well as on the outer surface. Conclusion This project has shown that silica carrier platforms may be used as an alternative approach to generating polymeric solid dispersions of amorphous drugs exhibiting enhanced solubility.

Solid dispersions with hydrogenated castor oil increase solubility, dissolution rate and intestinal absorption of praziquantel

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Nanotechnology-based drug delivery systems for treatment of hyperproliferative skin diseases - a review

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

FaSSIF-C, a Cholesterol containing biorelevant intestinal model medium for development and test of oral drug formulations

Biorelevante Medien sind entwickelt worden, um die Bedingungen im Magen-Darm-Trakt vor und nach der Mahlzeit zu imitieren. Mit FaSSIF und FeSSIF wurden Medien eingeführt, die nicht nur die pH- und Puffer-Kapazität des Dünndarms widerspiegeln, sondern auch Lipid und physiologische Tensid-Arten enthalten. Diese Medien (FaSSIF-V2 und FaSSlFmod6.5) wurden für Bioverfügbarkeitstudien in der Medikamentenentwicklung im Laufe der Jahre kontinuierlich weiterentwickelt. Dennoch sind die auf dem Markt verfügbaren Medien immer noch nicht in der Lage, die realen physiologischen Bedingungen zu simulieren. In der jetzigen Zusammensetzung sind nicht alle Kompetenten enthalten, welche natürlicher Weise im Duodenum vorkommen. Darüber hinaus wird nur eine 1:5 Verdünnung von FeSSIF zu FaSSIF angenommen, die individuelle Wasserzufuhr bei Medikamentengabe wird hierdurch jedoch nur eingeschränkt simuliert, obwohl diese von Patient zu Patient schwanken kann. rnZiel dieser Dissertation war die Verbesserung der Vorhersage der Auflösung und Absorption lipophiler Arzneistoffe durch Simulation der Bedingungen im zweiten Teil des Zwölffingerdarms mit neuen biorelevanten Medien, sowie unter Einwirkung zusätzlicher Detergention als Wirkstoffträger. rnUm den Effekt der Verdünnungsrate und Zeit im Dünndarm zu untersuchen, wurde die Entwicklung der Nanopartikel in der Magen-Darm-Flüssigkeit FaSSIFmod6.5 zu verschiedenen Zeitpunkten und Wassergehalten untersucht. Dafür wurden kinetische Studien an verschieden konzentrierten Modellmedien nach Verdünnungssprung untersucht. Das Modell entspricht der Vermischung der Gallenflüssigkeit mit dem Darminhalt bei variablem Volumen. Die Ergebnisse zeigen, dass Art und Größe der Nanopartikel stark von Verdünnung und Einirkungszeit abhängen. rnrnDie menschliche Darmflüssigkeit enthält Cholesterin, welches in allen früheren Modellmedien fehlt. Daher wurden biokompatible und physiologische Modellflüssigkeiten, FaSSIF-C, entwickelt. Der Cholesteringehalt von FaSSIF - 7C entspricht der Gallenflüssigkeit einer gesunden Frau, FaSSIF - 10C der einer gesunden männlichen Person und FaSSIF - 13C der in einigen Krankheitszuständen. Die intestinale Teilchen-Struktur-Untersuchung mit dynamische Lichtstreuung (DLS) und Neutronen-Kleinwinkelstreuung (SANS) ergab, dass die Korngröße von Vesikeln mit zunehmender Cholesterin-Konzentration abnahm. Zu hohe Cholesterin-Konzentration bewirkte zusätzlich sehr große Partikel, welche vermutlich aus Cholesterin-reichen “Disks“ bestehen. Die Löslichkeiten einiger BCS Klasse II Wirkstoffe (Fenofibrat, Griseofulvin, Carbamazepin, Danazol) in diesen neuen Medien zeigten, dass die Löslichkeit in unterschiedlicher Weise mit der Cholesteringehalt zusammen hing und dieser Effekt selektiv für die Droge war. rnDarüber hinaus wurde die Wirkung von einigen Tensiden auf die kolloidale Struktur und Löslichkeit von Fenofibrat in FaSSIFmod6.5 und FaSSIF -7C untersucht. Struktur und Löslichkeit waren Tensid- und Konzentrations-abhängig. Im Falle von FaSSIFmod6.5 zeigten die Ergebnisse eine dreifache Verzweigung der Lösungswege. Im Bereich mittlerer Tensidkonzentration wurde eine Löslichkeitslücke der Droge zwischen der Zerstörung der Galle-Liposomen und der Bildung von Tensid-reichen Mizellen beobachtet. In FaSSIF - 7C, zerstörten Tenside in höherer Konzentration die Liposomenstruktur trotz der allgemeinen Stabilisierung der Membranen durch Cholesterin. rnDie in dieser Arbeit vorgestellten Ergebnisse ergeben, dass die Anwesenheit von Cholesterin als eine fehlende Komponente der menschlichen Darmflüssigkeit in biorelevanten Medien wichtig ist und dazu beitragen kann, das in vivo Verhalten schwerlöslicher Arzneistoffe im Körper besser vorhersagen zu können. Der Verdünnungsgrad hat einen Einfluss auf die Nanopartikel-Struktur und Tenside beeinflussen die Löslichkeit von Medikamenten in biorelevanten Medien: Dieser Effekt ist sowohl von der Konzentration das Tensids abhängig, als auch dessen Typ.rnrn

Liposome formulation of poorly water soluble drugs:optimisation of drug loading and ESEM analysis of stability

Liposomes due to their biphasic characteristic and diversity in design, composition and construction, offer a dynamic and adaptable technology for enhancing drug solubility. Starting with equimolar egg-phosphatidylcholine (PC)/cholesterol liposomes, the influence of the liposomal composition and surface charge on the incorporation and retention of a model poorly water soluble drug, ibuprofen was investigated. Both the incorporation and the release of ibuprofen were influenced by the lipid composition of the multi-lamellar vesicles (MLV) with inclusion of the long alkyl chain lipid (dilignoceroyl phosphatidylcholine (C 24PC)) resulting in enhanced ibuprofen incorporation efficiency and retention. The cholesterol content of the liposome bilayer was also shown to influence ibuprofen incorporation with maximum ibuprofen incorporation efficiency achieved when 4 μmol of cholesterol was present in the MLV formulation. Addition of anionic lipid dicetylphosphate (DCP) reduced ibuprofen drug loading presumably due to electrostatic repulsive forces between the carboxyl group of ibuprofen and the anionic head-group of DCP. In contrast, the addition of 2 μmol of the cationic lipid stearylamine (SA) to the liposome formulation (PC:Chol - 16 μmol:4 μmol) increased ibuprofen incorporation efficiency by approximately 8%. However further increases of the SA content to 4 μmol and above reduced incorporation by almost 50% compared to liposome formulations excluding the cationic lipid. Environmental scanning electron microscopy (ESEM) was used to dynamically follow the changes in liposome morphology during dehydration to provide an alternative assay of liposome stability. ESEM analysis clearly demonstrated that ibuprofen incorporation improved the stability of PC:Chol liposomes as evidenced by an increased resistance to coalescence during dehydration. These finding suggest a positive interaction between amphiphilic ibuprofen molecules and the bilayer structure of the liposome. © 2004 Elsevier B.V. All rights reserved.

Amino acids in oral drug delivery:salts, ion-pairs and transcriptomics

Oral drug delivery is considered the most popular route of delivery because of the ease of administration, availability of a wide range of dosage forms and the large surface area for drug absorption via the intestinal membrane. However, besides the unfavourable biopharmaceutical properties of the therapeutic agents, efflux transporters such as Pglycoprotein (P-gp) and multiple resistance proteins (MRP) decrease the overall drug uptake by extruding the drug from the cells. Although, prodrugs have been investigated to improve drug partitioning by masking the polar groups covalently with pre-moieties promoting increased uptake, they present significant challenges including reduced solubility and increased toxicity. The current work investigates the use of amino acids as ion-pairs for three model drugs: indomethacin (weak acid), trimethoprim (weak base) and ciprofloxacin (zwitter ion) in an attempt to improve both solubility and uptake. Solubility was studied by salt formation while creating new routes for uptake across the membranes via amino acids transporter proteins or dipeptidyl transporters was the rationale to enhance absorption. New salts were prepared for the model drugs and the oppositely charged amino acids by freeze drying and they were characterised using FTIR, 1HNMR, DSC, SEM, pH solubility profile, solubility and dissolution. Permeability profiles were assessed using an in vitro cell based method; Caco-2 cells and the genetic changes occurring across the transporter genes and various pathways involved in the cellular activities were studied using DNA microarrays. Solubility data showed a significant increase in drug solubility upon preparing the new salts with the oppositely charged counter ions (ciprofloxacin glutamate salt exhibiting 2.9x103 fold enhancement when compared to the free drug). Moreover, permeability studies showed a 3 fold increase in trimethoprim and indomethacin permeabilities upon ion-pairing with amino acids and more than 10 fold when the zwitter ionic drug was paired with glutamic acid. Microarray data revealed that trimethoprim was absorbed actively via OCTN1 transporters while MRP7 is the main transporter gene that mediates its efflux. The absorption of trimethoprim from trimethoprim glutamic acid ion-paired formulations was affected by the ratio of glutamic acid in the formulation which was inversely proportional to the degree of expression of OCTN1. Interestingly, ciprofloxacin glutamic acid ion-pairs were found to decrease the up-regulation of ciprofloxacin efflux proteins (P-gp and MRP4) and over-express two solute carrier transporters; (PEPT2 and SLCO1A2) suggesting that a high aqueous binding constant (K11aq) enables the ion-paired formulations to be absorbed as one entity. In conclusion, formation of ion-pairs with amino acids can influence in a positive way solubility, transfer and gene expression effects of drugs.

Pluronic F127-modified liposome-containing tacrolimus-cyclodextrin inclusion complexes:improved solubility, cellular uptake and intestinal penetration

Objective The aim of this study was to investigate Pluronic F127-modified liposome-containing cyclodextrin (CD) inclusion complex (FLIC) for improving the solubility, cellular uptake and intestinal penetration of tacrolimus (FK 506) in the gastrointestinal (GI) tract. Methods Molecular modelling was performed to screen the optimal CD for the solubilization of FK 506. FLIC was prepared by thin-lipid film hydration with the inclusion complex solutions followed by membrane extrusion. Dilution tests were conducted in simulated gastric fluids and phosphate-buffered solution of sodium taurocholate to investigate the solubility improvement of FK506. The cellular uptake of nanocarriers was studied in Caco-2 cells, and intestinal mucous membrane penetration in the GI tract was evaluated in Sprague-Dawley rats. Key findings The results showed that β-CD had the strongest binding energy with the guest molecule among the CDs. The prepared FLIC has an average diameter of 180.8 ± 8.1 nm with a spherical shape. The solubility and cellular uptake of FK 506 was greatly improved by the incorporation of CD complexes in the Pluronic F127-modified liposomes. Intestinal mucous membrane penetration was also significantly improved by the preparation of FLIC. Conclusion With improved drug solubility and intestinal mucous membrane penetration, FLIC shows a promising oral delivery system for FK 506. © 2013 Royal Pharmaceutical Society.

Encapsulation of Hydrocortisone and Mesalazine in Zein Microparticles

Zein was investigated for use as an oral-drug delivery system by loading prednisolone into zein microparticles using coacervation. To investigate the adaptability of this method to other drugs, zein microparticles were loaded with hydrocortisone, which is structurally related to prednisolone; or mesalazine, which is structurally different having a smaller LogP and ionizable functional groups. Investigations into the in vitro digestibility, and the electrophoretic profile of zein, and zein microparticles were conducted to shed further insight on using this protein as a drug delivery system. Hydrocortisone loading into zein microparticles was comparable with that reported for prednisolone, but mesalazine loading was highly variable. Depending on the starting quantities of hydrocortisone and zein, the average amount of microparticles equivalent to 4 mg hydrocortisone, (a clinically used dose), ranged from 60-115 mg, which is realistic and practical for oral dosing. Comparatively, an average of 2.5 g of microparticles was required to deliver 250 mg of mesalazine (a clinically used dose), so alternate encapsulation methods that can produce higher and more precise mesalazine loading are required. In vitro protein digestibility revealed that zein microparticles were more resistant to digestion compared to the zein raw material, and that individual zein peptides are not preferentially coacervated into the microparticles. In combination, these results suggest that there is potential to formulate a delivery system based on zein microparticles made using specific subunits of zein that is more resistant to digestion as starting material, to deliver drugs to the lower gastrointestinal tract.