Molecular Properties of Ibuprofen and Its Solid Dispersions with Eudragit RL100 Studied by Solid-State Nuclear Magnetic Resonance

Purpose The aim of this study was to investigate, at a molecular level, the structural and dynamic properties of the acidic and sodium salt forms of ibuprofen and their solid dispersions with Eudragit RL-100, obtained by two different preparation methods (physical mixtures and coevaporates), which may affect the release properties of these drugs in their dispersed forms.Methods ¹H and ¹³C high-resolution solid-state nuclear magnetic resonance techniques, including single-pulse excitation magic-angle spinning, cross-polarization magic-angle spinning, and other selective 1D spectra, as well as more advanced 2D techniques Frequency Switched Lee-Goldburg HETeronuclear CORrelation (FSLG-HETCOR) and Magic Angle Spinning -J- Heteronuclear Multiple-Quantum Coherence (MAS-J-HMQC) and relaxation time measurements were used.Results A full assignment of ¹³C resonances and precise ¹H chemical shift values were achieved for the first time for the two forms of ibuprofen that showed very different interconformational dynamic behavior; drug–polymer interactions were observed and characterized in the coevaporates of the two forms but were much stronger for the acidic form.Conclusions A combined analysis of several high-resolution solid-state nuclear magnetic resonance experiments allowed the investigation of the structural and dynamic properties of the pure drugs and of the solid dispersions with the polymer, as well as of the degree of mixing between drug and polymer and of the chemical nature of their interaction. Such information could be related to the in vitro drug release profiles observed for the tested coevaporates.     

Dissolution enhancement of felodipine by amorphous nanodispersions using an amphiphilic polymer: insight into the role of drug–polymer interactions on drug dissolution

Context: Felodipine, a poorly soluble drug, is widely used in the treatment of angina pectoris and hypertension.

Objective: This study aimed at the preparation of amorphous solid dispersion (SD) of felodipine using an amphiphilic polymer, soluplus, for the potential enhancement in solubility of the drug.

Materials and methods: Solid dispersions with varying proportions of drug and soluplus were prepared and the rate and extent of dissolution from SDs was compared with that of the pure drug. FT-IR and ¹H NMR spectroscopic analysis were carried out to examine the formation mechanism of SDs. Various techniques were used for solid state characterization of designed SDs.

Results: Formation of amorphous solid dispersions with particle size in nanometer range indicated suitability of polymer and method used in the preparation. FT-IR and ¹H NMR spectroscopy revealed that soluplus was involved in strong hydrogen bonding with felodipine molecules which resulted in the conversion of crystalline felodipine into amorphous form. Solid dispersion with 1:10 drug/polymer ratio showed more than 90% drug dissolution in 30?min whereas pure felodipine showed less than 19% drug dissolution in 1?h.

Discussion and conclusion: Amorphous SDs of felodipine were prepared using soluplus resulting in substantial enhancement in the rate and extent of dissolution of felodipine.     

Preparation of Controlled-Release Coevaporates of Dipyridamole by Loading Neutral Pellets in a Fluidized-Bed Coating System

Purpose. The purpose of this study was to demonstrate that it is possible to prepare controlled-release drug-polymer coevaporates on an industrial scale, omitting the recovery problems and the milling and sieving processes encountered when coevaporates are prepared by the conventional solvent-evaporation technique. Methods. Controlled-release coevaporates were prepared by spraying organic solutions of dipyridamole-Eudragit^® blends onto neutral pellets using the fluidized-bed coating method. Enteric acrylic polymers Eudragit^® L100-55, L, and S were used as dispersing agents and drug/polymer ratio 2:8 was selected for all formulations. Polarized light microscopy, X-ray diffraction spectroscopy, and differential scanning calorimetry were used to determine whether the drug was amorphous or crystalline in the coating films. Moreover, in vitro dissolution tests were performed on the dipyridamole coated pellets in test media simulating the pH variations in the GI tract and the results were compared to the release data obtained from coevaporates prepared by the conventional solvent-evaporation method. Results. All the results clearly indicate that dipyridamole is amorphous in the coating films deposited on neutral pellets as well as in coevaporate particles obtained by the conventional solvent-evaporation method. When the release patterns of the dipyridamole coated pellets are compared to those of the drug coevaporate particles prepared with the same enteric acrylic polymers, the results show similar dissolution trends. Conclusions. The results obtained indicate that pelletization can be considered as a method of choice for pilot plant and/or full-scale production of controlled-release dosage forms based on the formation of amorphous solid dispersions.     

Physicochemical Characterization of Felodipine-Kollidon VA64 Amorphous Solid Dispersions Prepared by Hot-Melt Extrusion

To improve the dissolution and hence the oral bioavailability, amorphous felodipine (FEL) solid dispersions (SDs) with Kollidon® VA 64 (PVP/VA) were prepared. Hot-melt extrusion was employed with an extruding temperature below the melting point (T_m) of FEL. X-ray powder diffraction (XRPD) and ¹³C CP/MAS nuclear magnetic resonance (NMR) measurements show that the extrudates are amorphous. The intermolecular interaction between FEL and PVP/VA in SDs was investigated by Fourier transform infrared spectroscopy, ¹⁵N CP/MAS NMR, and ¹H high-resolution MAS NMR. Furthermore, a single glass transition temperature (T_g) was detected by differential scanning calorimetry in addition to a single ¹H T₁ or T_1rho relaxation time detected by ¹³C NMR signals. These results confirm that the extru-dates contain FEL dispersed into the polymer matrix at a molecular level with no detectable phase separation. This molecular-scale mixing results in a significantly faster dissolution rate compared with the pure crystalline FEL. Additionally, the molecular-scale mixing prevents the amorphous drug from recrystallizing even after being stored at 40°C/75% Relative Humidity for 2 months.     

Determination of the Composition of Delavirdine Mesylate Polymorph and Pseudopolymorph Mixtures Using 13C CP/MAS NMR

Purpose. The application of solid-state nuclear magnetic resonance for the quantitation of relative amounts of delavirdine mesylate (DLV-M) polymorph and/or pseudopolymorph in their binary mixtures is presented. Methods. ¹³C CP (cross-polarization)/MAS (magic angle spinning) NMR techniques were employed for quantitation. Results. ¹³C CP/MAS NMR spectra of three DLV-M solid forms (VIII, XI, and XII) revealed distinct differences in chemical shifts and peak splitting characteristics. Resonances of isopropyl methyl carbons of DLV-M were diagnostic of each form; resonance intensities were utilized to determine the composition of two series of DLV-M solid form mixtures (VIII and XI; XII and XI) over a dynamic concentration range (1–50%). The empirical detection limit of form VIII, or XII, in a dominant form XI environment was about 2–3% (w/w). Quantitations were obtained using appropriate analytical procedures, which took into account the differences of T_CH and T_lpH between the two forms. Quantitative results obtained using either the peak area or peak height were examined, and, in general, were satisfactory. Conclusions. The methodology and analytical procedure developed in this study are generally applicable to quantitative analysis using ¹³C CP/MAS NMR for pharmaceutical solids, including bulk drug substances, and dosage forms. Reliable measurement of NMR relaxation times (T_1pH) and CP rate constants (T_CH) of individual forms is a critical component in this application.     

Characterization of Three Crystalline Forms (VIII,XI, and XII) and the Amorphous Form (V) of Delavirdine Mesylate Using 13C CP/MAS NMR

Purpose. The application of solid-state nuclear magnetic resonance (NMR) characterization of three crystalline forms (VIII, XI, XII) and the amorphous form V of delavirdine mesylate (DLV-M) is presented. Methods. Conventional ¹³C CP (cross-polarization)/MAS (magic angle spinning) NMR and related spectral editing methods were employed. NMR relaxation times (T_1pH, T_1H, and T_1C) were also measured. Results. Distinctly different spectral features among the four solid forms were observed, indicating high sensitivity of ¹³C NMR to the variations in solid structure. Assessment based on NMR data suggests that both anhydrous forms VIII and XI may contain one molecule per asymmetric unit. DLV may adopt a similar molecular conformation in the two forms. In contrast, form XII is found to consist of two molecules per asymmetric unit. Molecule conformation of DLV in forms VIII, XI, and XII is altered from the dominant conformer in solution. The amorphous form V may contain DLV molecules of a variety of conformations. NMR relaxation times (T_lpH, T_1H, and T_1C) provide valuable information about the motional characteristics in these solids. Values and the rank order of T_lpH, T_1H, and T_1C also reveal significant differences in local environments and the short range order among the four forms. Conclusions. Four solid forms of DLV-M (V, VIII, XI. and XII) can be distinctly differentiated by ¹³C CP/MAS NMR spectroscopy and their structural difference can be partially revealed without obtaining single crystal data. NMR relaxation times reveal motion dynamics and aid structural elucidation for these forms.     

Antioxidant activity and photostability assessment of trans-resveratrol acrylate microspheres

Trans-resveratrol (RSV) was microencapsulated in Eudragit^® RS100 and RL100 resin blends. Lyophilized microspheres were characterized in the solid state for their micromeritic properties and drug loading. FT-IR, PXRD, and DSC analyzes suggested that RSV formed an intimate microcrystalline dispersion within the polymer network, also confirmed by SEM analysis. This produced a reduced degradation of RSV after storage at 40?°C, compared to the neat drug, and a protection of the drug from UV light-induced trans-cis isomerization (60% intact drug was found after 60?s irradiation at 350?nm, compared to 37% for the pure drug). Solubility and in vitro dissolution studies indicated that microencapsulation did not improve the dissolution pattern of RSV in simulated gastric and intestinal aqueous fluids. Evaluation of the in vitro antioxidant activity showed that, compared to the neat drug in aqueous solution, RSV loaded in the microspheres retained for a longer time, up to 22 days of incubation, the initial ORAC capacity. The present study thus demonstrated that Eudragit^® Retard resins can be used to easily produce micro-sized solid dispersions with RSV, for potential oral administration, contributing to ameliorate the physico-chemical stability and antioxidant activity of this compound.     

Solid-State NMR Investigation of Drug-Excipient Interactions and Phase Behavior in Indomethacin-Eudragit E Amorphous Solid Dispersions

Purpose

To investigate the nature of drug-excipient interactions between indomethacin (IMC) and methacrylate copolymer Eudragit® E (EE) in the amorphous state, and evaluate the effects on formulation and stability of these amorphous systems.

Methods

Amorphous solid dispersions containing IMC and EE were spray dried with drug loadings from 20% to 90%. PXRD was used to confirm the amorphous nature of the dispersions, and DSC was used to measure glass transition temperatures (T_g). ¹³C and ¹⁵N solid-state NMR was utilized to investigate changes in local structure and protonation state, while ¹H T₁ and T_1ρ relaxation measurements were used to probe miscibility and phase behavior of the dispersions.

Results

T_g values for IMC-EE solid dispersions showed significant positive deviations from predicted values in the drug loading range of 40–90%, indicating a relatively strong drug-excipient interaction. ¹⁵N solid-state NMR exhibited a change in protonation state of the EE basic amine, with two distinct populations for the EE amine at ?360.7 ppm (unprotonated) and ?344.4 ppm (protonated). Additionally, ¹H relaxation measurements showed phase separation at high drug load, indicating an amorphous ionic complex and free IMC-rich phase. PXRD data showed all ASDs up to 90% drug load remained physically stable after 2 years.

Conclusions

¹⁵N solid-state NMR experiments show a change in protonation state of EE, indicating that an ionic complex indeed forms between IMC and EE in amorphous solid dispersions. Phase behavior was determined to exhibit nanoscale phase separation at high drug load between the amorphous ionic complex and excess free IMC.

     

The application of absolute quantitative 1H NMR spectroscopy in drug discovery and development

ABSTRACT

Introduction: The identification of a drug candidate and its structural determination is the most important step in the process of the drug discovery and for this, nuclear magnetic resonance (NMR) is one of the most selective analytical techniques.

Area covered: The present review illustrates the various perspectives of absolute quantitative ¹H NMR spectroscopy in drug discovery and development. It deals with the fundamentals of quantitative NMR (qNMR), the physiochemical properties affecting qNMR, and the latest referencing techniques used for quantification. The precise application of qNMR during various stages of drug discovery and development, namely natural product research, drug quantitation in dosage forms, drug metabolism studies, impurity profiling and solubility measurements is elaborated. To achieve this, the authors explore the literature of NMR in drug discovery and development between 1963 and 2015. It also takes into account several other reviews on the subject.

Expert opinion: qNMR experiments are used for drug discovery and development processes as it is a non-destructive, versatile and robust technique with high intra and interpersonal variability. However, there are several limitations also. qNMR of complex biological samples is incorporated with peak overlap and a low limit of quantification and this can be overcome by using hyphenated chromatographic techniques in addition to NMR.     

On the inherent properties of Soluplus and its application in ibuprofen solid dispersions generated by microwave-quench cooling technology

Abstract

Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, or Soluplus^®, is a relatively new copolymer and a promising carrier of amorphous solid dispersions. Knowledge on the inherent properties of Soluplus^® (e.g. cloud points, critical micelle concentrations, and viscosity) in different conditions is relatively inadequate, and the application characteristics of Soluplus^®-based solid dispersions made by microwave methods still need to be clarified. In the present investigation, the inherent properties of a Soluplus^® carrier, including cloud points, critical micelle concentrations, and viscosity, were explored in different media and in altered conditions. Ibuprofen, a BCS class II non-steroidal anti-inflammatory drug, was selected to develop Soluplus^®-based amorphous solid dispersions using the microwave-quench cooling (MQC) method. Scanning electronic microscopy (SEM), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), Raman spectroscopy (RS), and Fourier transform infrared spectroscopy (FT-IR) were adopted to analyze amorphous properties and molecular interactions in ibuprofen/Soluplus^® amorphous solid dispersions generated by MQC. Dissolution, dissolution extension, phase solubility, equilibrium solubility, and supersaturated crystallization inhibiting experiments were performed to elucidate the effects of Soluplus^® on ibuprofen in solid dispersions. This research provides valuable information on the inherent properties of Soluplus^® and presents a basic understanding of Soluplus^® as a carrier of amorphous solid dispersions.     

大黄素固体分散体制备、表征与释药机制研究

摘要：目的 制备大黄素固体分散体，提高其体外溶出度并探究其释药机制。方法 采用分子对接技术，辅助筛选聚合物载体。以大黄素为原料药，Kollidon VA64为聚合物载体，采用热熔挤出工艺制备大黄素固体分散体。通过溶出仪测定其体外溶出，利用SEM，DCS和PXRD对原料药和固体分散体的表面形态和晶型进行表征，最后采用FTIR，NMR和分子动力学模拟对固体分散体的释药机制进行探究。结果 相较于大黄素原料药，大黄素固体分散体在4种介质中的溶出被明显改善，大黄素由结晶态转化为无定形态，药物与聚合物载体间形成了氢键。结论 固体分散体中药物晶型的转变和氢键的产生是改善药物体外溶出的主要因素。     

Initial Drug Dissolution from Amorphous Solid Dispersions Controlled by Polymer Dissolution and Drug-Polymer Interaction

Purpose

To identify the key formulation factors controlling the initial drug and polymer dissolution rates from an amorphous solid dispersion (ASD).

Methods

Ketoconazole (KTZ) ASDs using PVP, PVP-VA, HMPC, or HPMC-AS as polymeric matrix were prepared. For each drug-polymer system, two types of formulations with the same composition were prepared: 1. Spray dried dispersion (SDD) that is homogenous at molecular level, 2. Physical blend of SDD (80% drug loading) and pure polymer (SDD-PB) that is homogenous only at powder level. Flory-Huggins interaction parameters (χ) between KTZ and the four polymers were obtained by Flory-Huggins model fitting. Solution ¹³C NMR and FT-IR were conducted to investigate the specific drug-polymer interaction in the solution and solid state, respectively. Intrinsic dissolution of both the drug and the polymer from ASDs were studied using a Higuchi style intrinsic dissolution apparatus. PXRD and confocal Raman microscopy were used to confirm the absence of drug crystallinity on the tablet surface before and after dissolution study.

Results

In solid state, KTZ is completely miscible with PVP, PVP-VA, or HPMC-AS, demonstrated by the negative χ values of ?0.36, ?0.46, ?1.68, respectively; while is poorly miscible with HPMC shown by a positive χ value of 0.23. According to solution ¹³C NMR and FT-IR studies, KTZ interacts with HPMC-AS strongly through H-bonding and dipole induced interaction; with PVPs and PVP-VA moderately through dipole-induced interactions; and with HPMC weakly without detectable attractive interaction. Furthermore, the “apparent” strength of drug-polymer interaction, measured by the extent of peak shift on NMR or FT-IR spectra, increases with the increasing number of interacting drug-polymer pairs. For ASDs with the presence of considerable drug-polymer interactions, such as KTZ/PVPs, KTZ/PVP-VA, or KTZ /HPMC-AS systems, drug released at the same rate as the polymer when intimate drug-polymer mixing was ensured (i.e., the SDD systems); while drug released much slower than the polymer when molecular level mixing or drug-polymer interaction was absent (SDD-PB systems). For ASDs without drug-polymer interaction (i.e., KTZ/HPMC systems), the mixing homogeneity had little impact on the release rate of either the drug or the polymer thus SDD and SDD-PB demonstrated the same drug or polymer release rate, while the drug released slowly and independently of polymer release.

Conclusions

The initial drug release from an ASD was controlled by 1) the polymer release rate; 2) the strength of drug-polymer interaction, including the intrinsic interaction caused by the chemistry of the drug and the polymer (measured by the χ value), as well as that the apparent interaction caused by the drug-polymer ratio (measure by the extent of peak shift on spectroscopic analysis); and 3) the level of mixing homogeneity between the drug and polymer. In summary, the selection of polymer, drug-polymer ratio, and ASD processing conditions have profound impacts on the dissolution behavior of ASDs.

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Graphical Abstract Relationship between initial drug and polymer dissolution rates from amorphous solid dispersions with different mixing uniformity and drug-polymer interactions

     

Physicochemical characterization and in vivo evaluation of flurbiprofen-loaded solid dispersion without crystalline change

To develop a novel flurbiprofen-loaded solid dispersion without crystalline change, various flurbiprofen-loaded solid dispersions were prepared with water, sodium carboxylmethyl cellulose (Na-CMC), and Tween 80. The effect of Na-CMC and Tween 80 on aqueous solubility of flurbiprofen was investigated. The physicochemical properties of solid dispersions were investigated using SEM, DSC, and X-ray diffraction. The dissolution and bioavailability in rats were evaluated compared to commercial product. Unlike conventional solid dispersion systems, the flurbiprofen-loaded solid dispersion gave a relatively rough surface and changed no crystalline form of drug. These solid dispersions were formed by attaching hydrophilic carriers to the surface of drug without crystal change, resulting in changing the hydrophobic drug to hydrophilic form. Furthermore, the flurbiprofen-loaded solid dispersion at the weight ratio of flurbiprofen/Na-CMC/Tween 80 of 6/2.5/0.5 improved ～ 60-fold drug solubility. It gave higher AUC, T_max, and C_max compared to commercial product. The solid dispersion improved almost 1.5-fold bioavailability of drug compared to commercial product in rats. Thus, the flurbiprofen-loaded solid dispersion would be useful to deliver poorly water-soluble flurbiprofen with enhanced bioavailability without crystalline change.     

Elucidation of Solution State Complexation in Wet-Granulated Oven-Dried Ibuprofen and β-Cyclodextrin: FT-IR and 1H-NMR Studies

The effect of oven-dried wet granulation on the complexation of β-cyclodextrin with ibuprofen (IBU) in solution was investigated using Fourier transform infrared spectroscopy (FT-IR), proton nuclear magnetic resonance (¹H NMR), and molecular modeling. Granulation was carried out using 5 mL of three different granulating solvents; water, ethanol (95% v/v), and isopropanol and the granules were oven-dried at 60°C for 2 h. The granules were compared to oven-dried physical mixture and conventionally prepared complex. Phase solubility study was performed to investigate the stability of the granulation-formed complexes in solution. FT-IR was used to examine the complexation in the granules while ¹H NMR, and molecular modeling studies were carried out to determine the mechanism of complexation in the water-prepared granules. The solubility studies suggested a 1:1 complex between IBU and βCD. It also showed that the stability of the complex in solution was in the following order with respect to the granulating solvents: ethanol > water > isopropanol. The FT-IR study revealed a shift in the carboxylic acid stretching band and decrease in the intensities of the C-H bending bands of the isopropyl group and the out-of-plane aromatic ring, of IBU, in granules compared to the oven-dried physical mixture. This indicated that granules might have some extent of solid state complexation that could further enhance dissolution and the IBU–βCD solution state complexation. ¹H NMR showed that water prepared oven-dried granules had a different ¹H NMR spectrum compared to similarly made oven-dried physical mixture, indicative of complexation in the former. The ¹H NMR and the molecular modeling studies together revealed that solution state complexation from the granules occurred by inclusion of the isopropyl group together with part of the aromatic ring of IBU into the βCD cavity probably through its wider side. These results indicate that granulation process induced faster complexation in solution which enhances the solubility and the dissolution rate of poorly soluble drugs. The extent of complexation in the granules was dependent on the type of solvent used.     

Hyperbranched polymers as drug carriers: microencapsulation and release kinetics

The aim of this work was to study the feasibility of hyperbranched polymers as drug carriers by employing different microparticle formation methods and the influence of loading methods on release kinetics. Commercially available hyperbranched polyester (Perstorp) and three polyesteramides (DSM) were loaded with the pharmaceutical acetaminophen. The gas antisolvent precipitation (GAS), the coacervation, and the particles from gas saturated solutions (PGSS) are among conventional processes that were used to prepare microparticles of drug-loaded hyperbranched polyesters for the first time. For preparing solid dispersions of drug-loaded hyperbranched polyesteramides the solvent method was applied. Infrared (IR) and differential thermal analysis (DTA) studies suggest that acetaminophen is partly dissolved in the polymer matrix and partly crystallized outside the polymer matrix. For acetaminophen-loaded polyesters prepared by the GAS method, the presence of free drugs is predominant when compared to microparticles prepared by the coacervation method. This event disappears for microparticles prepared by the PGSS method. Moreover, the release of drug from drug-loaded Bol-GAS is biphasic, where the initial burst (48%), indicating the presence of unincorporated drugs, is followed by a slow-release phase, suggesting the diffusion of drug through polymer matrices. The release of drugs from drug-loaded Bol-PGSS do not show this behavior since the drug is better dissolved or dispersed in polymer matrices. In the case of drug-loaded polyesteramides, coevaporates prepared from 3 hyperbranched structures (H1690, H1200, and H1500) using the solvent method result in different release kinetics. The hydrophobic characteristic of hyperbranched polyesteramide H1500 shows the biphasic release kinetic whereas the drug released from hydrophilic matrices H1690 and H1200 exhibits fast release comparable to that of pure drug.     

Hyperbranched Polymers as Drug Carriers: Microencapsulation and Release Kinetics

The aim of this work was to study the feasibility of hyperbranched polymers as drug carriers by employing different microparticle formation methods and the influence of loading methods on release kinetics. Commercially available hyperbranched polyester (Perstorp) and three polyesteramides (DSM) were loaded with the pharmaceutical acetaminophen. The gas antisolvent precipitation (GAS), the coacervation, and the particles from gas saturated solutions (PGSS) are among conventional processes that were used to prepare microparticles of drug-loaded hyperbranched polyesters for the first time. For preparing solid dispersions of drug-loaded hyperbranched polyesteramides the solvent method was applied. Infrared (IR) and differential thermal analysis (DTA) studies suggest that acetaminophen is partly dissolved in the polymer matrix and partly crystallized outside the polymer matrix. For acetaminophen-loaded polyesters prepared by the GAS method, the presence of free drugs is predominant when compared to microparticles prepared by the coacervation method. This event disappears for microparticles prepared by the PGSS method. Moreover, the release of drug from drug-loaded Bol-GAS is biphasic, where the initial burst (48%), indicating the presence of unincorporated drugs, is followed by a slow-release phase, suggesting the diffusion of drug through polymer matrices. The release of drugs from drug-loaded Bol-PGSS do not show this behavior since the drug is better dissolved or dispersed in polymer matrices. In the case of drug-loaded polyesteramides, coevaporates prepared from 3 hyperbranched structures (H1690, H1200, and H1500) using the solvent method result in different release kinetics. The hydrophobic characteristic of hyperbranched polyesteramide H1500 shows the biphasic release kinetic whereas the drug released from hydrophilic matrices H1690 and H1200 exhibits fast release comparable to that of pure drug.     

Silymarin-solid dispersions: characterization and influence of preparation methods on dissolution

The influence of preparation methodology of silymarin solid dispersions using a hydrophilic polymer on the dissolution performance of silymarin was investigated. Silymarin solid dispersions were prepared using HPMC E 15LV by kneading, spray drying and co-precipitation methods and characterized by FTIR, DSC, XRPD and SEM. Dissolution profiles were compared by statistical and model independent methods. The FTIR and DSC studies revealed weak hydrogen bond formation between the drug and polymer, while XRPD and SEM confirmed the amorphous nature of the drug in co-precipitated solid dispersion. Enhanced dissolution compared to pure drug was found in the following order: co-precipitation > spray drying > kneading methodology (p < 0.05). All preparation methods enhanced silymarin dissolution from solid dispersions of different characteristics. The co-precipitation method proved to be best and provided a stable amorphous solid dispersion with 2.5 improved dissolution compared to the pure drug.     

A 31P CP/MAS NMR Study on Dehydration of Disodium Clodronate Tetrahydrate

Purpose. ³¹P CP/MAS NMR is used to characterize stability and changes in solid state properties of disodium clodronate tetrahydrate upon variable temperature and slow dehydration. Methods. Variable temperature ³¹P CP/MAS NMR spectroscopy. Results. A fast rise in temperature leads to loss of lattice waters and produces an averaged structure characterized by a single ³¹P NMR resonance at 398 K. Slow room temperature dehydration converts the crystalline form to an anhydrous structure with two non-equivalent phosphorus atoms. The molecular skeleton of clodronate is stable within the temperature range 296 K-398 K of experiments. Rehydration of the anhydrous samples at room temperature restores the crystalline tetrahydrate form verified by a ^3IP CP/MAS NMR spectrum similar to that of a virginal sample. Conclusions. Solid state NMR is a method which can offer both molecular and crystal scale information, when either bulk or dosage forms of a drug can be altered by temperature or by loss of lattice waters or solvents. The experiments are easy to perform, though time consuming, especially when low abundant nuclei are examined.     

Preparation, characterisation and photosensitivity studies of solid dispersions of diflunisal and Eudragit RS100 and RL100

Solid dispersions of diflunisal (DIF) with Eudragit RS100 (RS) and RL100 (RL) with different drug-to-polymer ratios were prepared by a solvent method (coevaporates) and were characterised in the solid state in comparison with the corresponding physical mixtures. The work was aimed at characterising the interactions occurring between DIF and RS or RL polymers, along with their influence on the in-vitro drug-dissolution pattern. The findings suggest that the drug did not change its crystalline form within the polymer network. Drug dispersion in the polymer matrix strongly influences its dissolution rate, which appears slower and more gradual while increasing the polymer ratios. Moreover, DIF is known to be a photosensitive compound, and its photoproduct has been found to be a toxic agent. This can be evidenced by testing red blood cell membranes for their resistance to the osmotic shock induced by UVA irradiation in the presence of DIF. The presence of some DIF/RS coevaporates was shown to reduce significantly the drug photosensitization process towards cell membranes. This suggests the possibility of combining the design of a drug delivery system with a photoprotective strategy.