Formation mechanism of colloidal nanoparticles obtained from probucol/PVP/SDS ternary ground mixture

The purpose of this study was to investigate the formation mechanism of colloidal nanoparticles after dispersion of probucol/polyvinylpyrrolidone (PVP)/sodium dodecyl sulphate (SDS) ternary ground mixture (GM) into water. Probucol, PVP and SDS were mixed at a weight ratio of 1:3:1 and ground for 30 min with a vibrational rod mill. The morphology and physicochemical properties were investigated through high resolution scanning electron microscopy (SEM), environmental SEM, dynamic light scattering, (13)C NMR and zeta potential measurements. SEM images confirmed the presence of 20 nm size primary particles in the GM powder of probucol/PVP K17/SDS. Spherical nanoparticles with a size of around 100 nm, formed after dispersion of the GM into water, suggested an agglomeration of the primary particles. A further agglomeration of around 160 nm was observed with the stability experiment. Zeta potential and particle size measurements using latex beads revealed that PVPK 17/SDS complex was adsorbed on the probucol particle surface forming a layered structure. A similar agglomeration behavior was observed using the GM of probucol/PVP K12/SDS, though the molecular state of the PVPK 12/SDS complex at the particle surface was different from that of the PVPK 17/SDS complex. (13)C NMR results suggested that intermolecular interactions between PVP K12 and SDS did not reach the same level as the interactions between PVP K17 and SDS. This study proposed a formation mechanism of colloidal nanoparticles.     

Amorphous Stabilization and Dissolution Enhancement of Amorphous Ternary Solid Dispersions: Combination of Polymers Showing Drug–Polymer Interaction for Synergistic Effects

The purpose of this study was to understand the combined effect of two polymers showing drug–polymer interactions on amorphous stabilization and dissolution enhancement of indomethacin (IND) in amorphous ternary solid dispersions. The mechanism responsible for the enhanced stability and dissolution of IND in amorphous ternary systems was studied by exploring the miscibility and intermolecular interactions between IND and polymers through thermal and spectroscopic analysis. Eudragit E100 and PVP K90 at low concentrations (2.5%–40%, w/w) were used to prepare amorphous binary and ternary solid dispersions by solvent evaporation. Stability results showed that amorphous ternary solid dispersions have better stability compared with amorphous binary solid dispersions. The dissolution of IND from the ternary dispersion was substantially higher than the binary dispersions as well as amorphous drug. Melting point depression of physical mixtures reveals that the drug was miscible in both the polymers; however, greater miscibility was observed in ternary physical mixtures. The IR analysis confirmed intermolecular interactions between IND and individual polymers. These interactions were found to be intact in ternary systems. These results suggest that the combination of two polymers showing drug–polymer interaction offers synergistic enhancement in amorphous stability and dissolution in ternary solid dispersions. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3511–3523, 2014     

Structural evaluation of probucol nanoparticles in water by atomic force microscopy

Structural evaluation of probucol nanoparticles coground with polyvinylpyrrolidone K17 and sodium dodecyl sulfate for 90 min was performed by solid-state nuclear magnetic resonance (NMR) spectroscopy and atomic force microscopy (AFM) with force-distance curve analysis. The results of solid-state NMR indicated that the cogrinding changed crystalline probucol to amorphous form. The number-averaged mean heights of probucol particles in the ground mixture (GM) suspension were determined by AFM to be 6 and 15 nm for freshly prepared and 24h-stored samples, respectively. Nucleation and the subsequent crystal growth might have occurred after the GM was dispersed in water. The presence of probucol nanocrystals and agglomeration of the primary probucol nanoparticles were recognized by AFM force-distance curve analysis. AFM could be a promising tool to evaluate the structure of nanoparticles as well as their agglomeration behavior in aqueous media.     

Enhancement of oral bioavailability of an HIV-attachment inhibitor by nanosizing and amorphous formulation approaches

BMS-488043 is an HIV-attachment inhibitor that exhibited suboptimal oral bioavailability upon using conventional dosage forms prepared utilizing micronized crystalline drug substance. BMS-488043 is classified as a Biopharmaceutics Classification System (BCS) Class-II compound with a poor aqueous solubility of 0.04 mg/mL and an acceptable permeability of 178 nm/s in the Caco2 cell-line model. Two strategies were evaluated to potentially enhance the oral bioavailability of BMS-488043. The first strategy targeted particle size reduction through nanosizing the crystalline drug substance. The second strategy aimed at altering the drug's physical form by producing an amorphous drug. Both strategies provided an enhancement in oral bioavailability in dogs as compared to a conventional formulation containing the micronized crystalline drug substance. BMS-488043 oral bioavailability enhancement was 5- and 9-folds for nanosizing and amorphous formulation approaches, respectively. The stability of the amorphous coprecipitated drug prepared at different compositions of BMS-488043/polyvinylpyrrolidone (PVP) was evaluated upon exposure to stressed stability conditions of temperature and humidity. The drastic effect of exposure to humidity on conversion of the amorphous drug to crystalline form was observed. Additionally, the dissolution behavior of coprecipitated drug was evaluated under discriminatory conditions of different pH values to optimize the BMS-488043/PVP composition and produce a stabilized, amorphous BMS-488043/PVP (40/60, w/w) spray-dried intermediate (SDI), which was formulated into an oral dosage form for further development and evaluation.     

Stabilization and Improved <Emphasis Type="BoldItalic">in Vivo</Emphasis> Performance of Amorphous Etoricoxib using Gelucire 50/13

Purpose Amorphous drugs have gained importance because of their advantageous biopharmaceutical properties; however, their stabilization remains a challenge. The purpose of this work was to stabilize the amorphous form of etoricoxib (ET) by using a low excipient/drug ratio to improve drug dissolution and thus bioavailability. Methods The effect of Gelucire and polyvinylpyrrolidone (PVP) on stabilization and bioavailability of amorphous etoricoxib (AET) was studied. X-ray powder diffractometry, differential scanning calorimetry, and scanning electron microscopy were used to study the physical state of the drug. Dissolution studies were performed for melt granules of AET with Gelucire 50/13 (MG-AET) and solid dispersion with PVP (SDP) to differentiate dissolution performance. A stability study on samples was conducted for 3 months to evaluate the physical state of the drug and its dissolution in the formulation. The in vivo performance of the optimized and stable formulation of ET was evaluated in rat. Results Dissolution of MG-AET was significantly improved as compared to AET and SDP. Both factors, amorphization of drug and melt granulation with lipid, seemed to be important for improving dissolution. Stability data revealed that MG-AET was significantly advantageous for AET stabilization, whereas PVP was not. The amount of Gelucire required for the stabilization of one part of AET was 0.5 part (by weight), whereas even 1.5 part (by weight) of PVP failed to elicit the same result. The superior in vivo performance of MG-AET has been attributed to the altered physiochemical properties of AET and the presence of lipid in the system. Conclusion Gelucire can stabilize AET and improve its biopharmaceutical performance at a low excipient/drug ratio and may provide a better alternative to conventional stabilizers such as PVP.     

基于藻酸双酯钠的阿霉素/塞来昔布纳米药物晶体的制备及其抗肿瘤作用研究

目的 制备基于藻酸双酯钠的阿霉素/塞来昔布纳米药物晶体（PPDC）,并考察其体外抗肿瘤作用。方法 采用纳米沉淀法制得PPDC混悬液,分别表征PPDC的形态、粒径、电位、药物晶型、药物包载情况、释药性能,通过细胞摄取、细胞毒性、细胞侵袭、细胞黏附评价PPDC对4T1细胞的抑制作用。结果 PPDC混悬液呈规则球形,分散性良好,分布较窄,载药量高。塞来昔布、阿霉素以无定型稳定状态存在于PPDC中。PPDC在体外释放72 h时携载的药物能够有效释放。体外细胞实验表明,PPDC能被4T1细胞摄取,细胞毒作用具有浓度相关性,并显著抑制细胞侵袭和细胞黏附。结论 PPDC有效解决塞来昔布的难溶性、稳定剂毒性大等问题,与阿霉素共载实现两药协同抑制肿瘤细胞生长和转移的作用。     

Evaluation of molecular pharmaceutical and in‐vivo properties of spray‐dried isolated andrographolide—PVP

Objectives Andrographolide, a natural lipophilic molecule, has a wide range of pharmacological actions. However, due to low aqueous solubility, it has low oral bioavailability. The purpose of the study was to increase the solubility and dissolution rate of isolated andrographolide by formulating its solid dispersion. Method Solid dispersions were obtained by a spray‐drying technique using different ratios of drug to polyvinylpyrrolidine (PVP K‐30). Solid dispersions in compression with isolated drug and corresponding physical mixtures were characterized for various molecular pharmaceutical properties and subjected to stability study for up to 3 months. Key findings A five‐fold increase in saturation solubility of andrographolide with higher values of Q_5min (cumulative percentage release in 5 min) and lower values of t_75% (time required for 75% w/w drug release) for solid dispersion was observed in different dissolution mediums. This was attributed to the formation of amorphous nature and intermolecular hydrogen bonding between drug and PVP K‐30. The stability study showed there to be no significant change in molecular pharmaceutical properties and dissolution profile over the period of 3 months. Moreover, the in‐vivo study in Wistar albino rats also justified improvement in the therapeutic efficacy of andrographolide after solid dispersion. Conclusions This study demonstrates the utility of solid dispersion to improve primary and secondary pharmaceutical properties of andrographolide using PVP K‐30 as a carrier.     

Development of spray-dried co-precipitate of amorphous celecoxib containing storage and compression stabilizers

The purpose of this study was to obtain an amorphous system with minimum unit operations that will prevent recrystallization of amorphous drugs since preparation, during processing (compression) and further storage. Amorphous celecoxib, solid dispersion (SD) of celecoxib with polyvinyl pyrrollidone (PVP) and co-precipitate with PVP and carrageenan (CAR) in different ratios were prepared by the spray drying technique and compressed into tablets. Saturation solubility and dissolution studies were performed to differentiate performance after processing. Differential scanning calorimetry and X-ray powder difraction revealed the amorphous form of celecoxib, whereas infrared spectroscopy revealed hydrogen bonding between celecoxib and PVP. The dissolution profile of the solid dispersion and co-precipitate improved compared to celecoxib and amorphous celecoxib. Amorphous celecoxib was not stable on storage whereas the solid dispersion and co-precipitate powders were stable for 3 months. Tablets of the solid dispersion of celecoxib with PVP and physical mixture with PVP and carrageenan showed better resistance to recrystallization than amorphous celecoxib during compression but recrystallized on storage. However, tablets of co-precipitate with PVP and carageenan showed no evidence of crystallinity during stability studies with comparable dissolution profiles. This extraordinary stability of spray-dried co-precipitate tablets may be attributed to the cushioning action provided by the viscoelastic polymer CAR and hydrogen bonding interaction between celecoxib and PVP. The present study demonstrates the synergistic effect of combining two types of stabilizers, PVP and CAR, on the stability of amorphous drug during compression and storage as compared to their effect when used alone.     

Physicochemical Characterization of Hot Melt Extruded Bicalutamide–Polyvinylpyrrolidone Solid Dispersions

Solid molecular dispersions of bicalutamide (BL) and polyvinylpyrrolidone (PVP) were prepared by hot melt extrusion technology at drug‐to‐polymer ratios of 1:10, 2:10, and 3:10 (w/w). The solid‐state properties of BL, physical mixtures of BL/PVP, and hot melt extrudates were characterized using differential scanning calorimetry (DSC), powder X‐ray diffractometry (PXRD), Raman, and Fourier transform infrared (FTIR) spectroscopy. Drug dissolution studies were subsequently conducted on hot melt extruded solid dispersions and physical mixtures. All hot melt extrudates had a single T_g between the T_g of amorphous BL and PVP indicating miscibility of BL with PVP and the formation of solid molecular dispersions. PXRD confirmed the presence of the amorphous form of BL within the extrudates. Conversely, PXRD patterns recorded for physical mixtures showed sharp bands characteristic of crystalline BL, whereas DSC traces had a distinct endotherm at 196°C corresponding to melting of crystalline BL. Further investigations using DSC confirmed solid‐state plasticization of PVP by amorphous BL and hence antiplasticization of amorphous BL by PVP. Experimentally observed T_g values of physical mixtures were shown to be significantly higher than those calculated using the Gordon–Taylor equation suggesting the formation of strong intermolecular interactions between BL and PVP. FTIR and Raman spectroscopy were used to investigate these interactions and strongly suggested the presence of secondary interaction between PVP and BL within the hot melt extrudates. The drug dissolution properties of hot melt extrudates were enhanced significantly in comparison to crystalline BL and physical mixtures. Moreover, the rate and extent of BL release were highly dependent on the amount of PVP present within the extrudate. Storage of the extrudates confirmed the stability of amorphous BL for up to 12 months at 20°C, 40% RH whereas stability was reduced under highly humid conditions (20°C, 65% RH). Interestingly, BL recrystallization after storage under these conditions had no effect on the dissolution properties of the extrudates. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1322–1335, 2010     

Co-amorphous Formation Induced by Combination of Tranilast and Diphenhydramine Hydrochloride

In this study, we investigated the formation of a co-amorphous system of tranilast (TRL) and diphenhydramine hydrochloride (DPH), which are drugs used for treating allergies and inflammation. The crystallization from undercooled melts of the drugs and drug mixtures was evaluated by thermal analysis. Both drugs in the amorphous state underwent crystallization on heating, although the mixture remained in the amorphous state, indicating the formation of a co-amorphous system. The physicochemical properties of co-amorphous TRL-DPH prepared by the melting-cooling process were studied. The glass transition temperature of co-amorphous TRL-DPH deviated from the theoretical value. The enthalpy relaxation rate of the amorphous drugs, which reflected the molecular mobility, was reduced by the formation of a co-amorphous system. The intermolecular interactions between TRL and DPH in the co-amorphous system were measured by the change in the IR spectra. These results were consistent with the high physical stability. The co-amorphous sample remained in the amorphous state for over 30 days at 40°C, whereas the amorphous drugs showed rapid crystallization. Our findings demonstrate that TRL and DPH form a co-amorphous system, which dramatically decreases their crystallization without an excipient.     

Polymer incorporation method affects the physical stability of amorphous indomethacin in aqueous suspension

This study reports the potential of different polymers and polymer incorporation methods to inhibit crystallisation and maintain supersaturation of amorphous indomethacin (IND) in aqueous suspensions during storage. Three different polymers (poly(vinyl pyrrolidone) (PVP), hydroxypropyl methylcellulose (HPMC) and Soluplus® (SP)) were used and included in the suspensions either as a solid dispersion (SD) with IND or dissolved in the suspension medium prior to the addition of amorphous IND. The total concentrations of both IND and the polymer in the suspensions were kept the same for both methods of polymer incorporation. All the polymers (with both incorporation methods) inhibited crystallisation of the amorphous IND. The SDs were better than the predissolved polymer solutions at inhibiting crystallisation. The SDs were also better at maintaining drug supersaturation. SP showed a higher IND crystallisation inhibition and supersaturation potential than the other polymers. However, this depended on the method of addition. IND in SD with SP did not crystallise, nor did the SD generate any drug supersaturation, whereas IND in the corresponding predissolved SP solution crystallised (into the recently characterised η polymorphic form of the drug) but also led to a more than 20-fold higher IND solution concentration than that observed for crystalline IND. The ranking of the polymers with respect to crystallisation inhibition potential in SDs was SP ≫ PVP > HPMC. Overall, this study showed that both polymer type and polymer incorporation method strongly impact amorphous form stability and drug supersaturation in aqueous suspensions.     

Solid-State Surface Acidity and pH-Stability Profiles of Amorphous Quinapril Hydrochloride and Silicate Formulations

To determine the surface acidity and stability profiles of quinapril hydrochloride (QHCl) coground with silicates, solid-state equivalent pH (pHeq) of amorphous samples was measured by diffuse reflectance spectroscopy using pH indicator probes. Calibration curves for pH indicators were developed in buffer solutions. Amorphous samples with and without pH indicators were prepared by cryogrinding. Different pH grades of silicates and various QHCl/silicate ratios were used to make amorphous samples over a range of surface acidity. Diffuse reflectance spectra of amorphous samples were measured and pHeq was determined using the calibration curves of pH indicators developed in solution. Suspension pH of amorphous samples was also measured. The chemical stability of coground amorphous samples was assessed at 40°C and 0% or 48% RH. The chemical stability of neat amorphous quinapril lyophilized from solutions over a range of pH was also assessed at 40°C/0% RH and the reconstituted pH-stability profile of lyophiles was determined. For all silicate and QHCl/silicate amorphous samples, the same pH rank order was obtained based on pHeq and suspension pH. However, the pHeq was significantly lower than the corresponding suspension pH. Discrepancies between pH-stability profiles based on the pHeq and the suspension pH were observed. In general, the pHeq- and reconstituted pH-stability profiles were essentially identical, but the suspension pH-stability profile deviated from the reconstituted pH-stability profile by 2-3 pH units. The results indicate that solid-state surface acidity measurement provides a more accurate prediction of the effective surface acidity of amorphous formulations than the suspension pH. In conclusion, solid-state surface acidity measurement of excipients and solid formulations using pH indicator probes as surrogates can be used to determine the ionization state of the drug and to predict the chemical stability profile of the drug in actual solid formulations.     

Stability and Solubility of Celecoxib-PVP Amorphous Dispersions: A Molecular Perspective

PURPOSE: The purpose of the current study is to evaluate the solubility advantage offered by celecoxib (CEL) amorphous systems and to characterize and correlate the physical and thermodynamic properties of CEL and its amorphous molecular dispersions containing poly(vinylpyrrolidone) (PVP). METHODS: The measurement of crystalline content, glass transition temperatures, and enthalpy relaxation was performed using differential scanning calorimetry. Solubility and dissolutions studies were conducted at 37 degrees C to elucidate release mechanisms. Further, the amorphous systems were characterized by polarized light microscopy and X-ray powder diffraction studies. RESULTS: The PVP content has a prominent effect on the stability and solubility profiles of amorphous systems. A dispersion of 20% w/w PVP with CEL resulted in a maxima in terms of solubility enhancement and lowering of relaxation enthalpy. The release of drug from amorphous molecular dispersions was found to be drug-dependent and independent of the carrier. CONCLUSIONS: The solubility enhancement and enthalpy relaxation studies with respect to PVP concentration helped in a better prediction of role of carrier and optimization of concentration in the use of solid dispersions or amorphous systems. The drug release mechanism is drug-controlled rather than carrier-controlled.     

Recrystallization of Nifedipine and Felodipine from Amorphous Molecular Level Solid Dispersions Containing Poly(vinylpyrrolidone) and Sorbed Water

Purpose To compare the physical stability of amorphous molecular level solid dispersions of nifedipine and felodipine, in the presence of poly(vinylpyrrolidone) (PVP) and small amounts of moisture. Methods Thin amorphous films of nifedipine and felodipine and amorphous molecular level solid dispersions with PVP were stored at various relative humidities (RH) and the nucleation rate was measured. The amount of water sorbed at each RH was measured using isothermal vapor sorption and glass transition temperatures (T _g) were determined using differential scanning calorimetry. The solubility of each compound in methyl pyrrolidone was measured as a function of water content. Results Nifedipine crystallizes more easily than felodipine at any given polymer concentration and in the presence of moisture. The glass transition temperatures of each compound, alone and in the presence of PVP, are statistically equivalent at any given water content. The nifedipine systems are significantly more hygroscopic than the corresponding felodipine systems. Conclusions Variations in the physical stability of the two compounds could not be explained by differences in T _g. However, the relative physical stability is consistent with differences in the degree of supersaturation of each drug in the solid dispersion, treating the polymer and water as a co-solvent system for each drug compound.     

Application of quartz crystal microbalance to study the impact of pH and ionic strength on protein-silicone oil interactions

The effect of adding a third polymer to immiscible binary solid dispersions was investigated. The model actives griseofulvin (GF), progesterone (PG) and phenindione (PD) were selected because they exemplify a key property of many poorly soluble molecules of having at least one hydrogen bonding acceptor moiety while not having any hydrogen bond donating moieties. Ternary solid dispersions of the drug, PVP (polyvinylpyrrolidone) (proton acceptor) and PHPMA (poly[2-hydroxypropyl methacrylate]) (proton acceptor and donor) were prepared by spray drying. Stability results showed that binary solid dispersions (API and PVP) of GF and PVP crystallized quickly while the amorphous form was not possible to prepare for PG and PD. The amorphous form was prolonged upon the incorporation of PHPMA in the solid dispersion (API, PHPMA and PVP). Based on measuring the melting points, the energy of mixing the drug with the polymer was calculated using the Flory-Huggins theory. The results showed that GF had the lowest free energy followed by PG and finally PD which agreed well with the stability results. These results suggest that the addition of a third polymer to immiscible binary solid dispersions can significantly improve the stability of the amorphous form.     

Raman and thermal analysis of indomethacin/PVP solid dispersion enteric microparticles

Indomethacin (IMC) and three types of poly-(vinylpyrrolidone) (PVP 12PF, PVP K30 and PVP K90) were studied in the form of solid dispersion, prepared with the solvent evaporation method, by spectroscopic (Raman, FT-IR, X-ray diffraction), thermal (differential scanning calorimetry, thermogravimetry, hot-stage microscopy), fractal and image analysis. Raman and FT-IR micro-spectroscopy indicated the occurrence of drug/polymer interaction and the presence of an amorphous form of IMC, as also resulting from X-ray diffractometry. Hot-stage microscopy suggested that the interaction between IMC and the polymer occurring on heating of a physical mixture, is common to other acidic compounds and causes a depression of the temperature of the appearance of a molten phase. Co-evaporated particles were coated by spray-congealing process with molten stearic acid for gastroprotection, but also for stabilization of the amorphous structure of the drug: the final particles were spherically shaped. Dissolution tests carried out on the final microparticles showed that the coating with stearic acid prevents IMC release at acidic pH and also protects against recovery of the IMC crystallinity, at least after 9 months of aging: the extent and mode of the release, before and after aging, overlap perfectly. The test revealed a notable improvement of the drug release rate from the solid dispersion at suitable pH, with respect to pure IMC. The comparison of the present solid dispersion with IMC/PVP (surface) solid dispersion obtained by freeze-drying of an aqueous suspension, where IMC maintained its crystalline state, revealed that there was no difference concerning the release rate, but suggested a superior quality of this last process as a mean of improving IMC availability for the easiness of preparation and stability, due to the absence of the amorphous state of the drug, as a possible instability source of the system. Finally, the coating with stearic acid is discussed as a determining process for the practical application of solid dispersions.     

Molecular Interaction among Probucol/PVP/SDS Multicomponent System Investigated by Solid-State NMR

Purpose Effects of polyvinylpyrrolidone (PVP) molecular weight on the solid-state intermolecular interactions among probucol/PVP/sodium dodecyl sulfate (SDS) ternary ground mixtures (GM) and the formation of nanoparticles were investigated by solid-state NMR spectroscopy.Materials and Methods Ternary GMs of probucol were prepared with PVP (K12, K17, K30 or K90) and SDS at a weight ratio of 1:3:1 and were ground for 15, 30 and 60 min. Solid-state interactions were evaluated using powder X-ray diffraction (PXRD) and solid-state cross polarization/magic angle spinning (CP/MAS) ¹³C NMR spectroscopy. A high resolution scanning electron microscopy (SEM) was employed to observe nanoparticles of probucol in the GM.Results The solid-state ¹³C CP/MAS NMR results indicate that the low molecular weight PVP interacts with probucol and SDS more strongly than the high molecular weight PVP in the ternary GM. This finding was consistent with the result that smaller drug nanoparticles were obtained using low molecular weight of PVP. SEM images of probucol/PVP K12/SDS confirmed the presence of nanoparticles (15–25 nm) in the GM.Conclusions Grinding-induced solid-state interactions among drug, PVP and SDS could be detected using solid state ¹³C NMR. The interactions in both probucol-PVP and PVP-SDS should occur simultaneously to generate nanometer-sized particles of probucol.     

Ternary amorphous composites of celecoxib, poly(vinyl pyrrolidone) and meglumine with enhanced solubility

The present study highlights the development of ternary amorphous composites to enhance the solubility of a poorly soluble crystalline drug, celecoxib (CEL). These systems comprised of an 'amorphous drug,' and its 'stabilizer' and 'solubilizer.' The ternary amorphous system of CEL, poly(vinyl pyrrolidone) (PVP) and meglumine (MEG) (7:2:1 w/w) enhanced CEL solubility by approximately equal to 10.2-fold over that for the crystalline drug, and maintained the thermodynamic stability of the amorphous drug. However, MEG alone was unable to stabilize the amorphous CEL against thermally-induced crystallization, and so gave no solubility advantage. The PVP-MEG combination provided a 'synergistic' enhancement of CEL solubility, as compared to their use alone in the amorphous systems. Phase-solubility studies provided greater insight into molecular mechanisms underlying stability and solubility of these amorphous systems. MEG exhibited phase-specific interaction with CEL molecules, when stabilized by PVP in the amorphous state. The higher solubility of CEL from ternary amorphous systems was also thermodynamically favored, as analyzed by van't Hoff plots. A possible molecular level interaction of MEG with PVP-stabilized amorphous CEL seems to be responsible for the solubility advantage of the CEL-PVP-MEG ternary amorphous system.     

Characterization of glass solutions of poorly water-soluble drugs produced by melt extrusion with hydrophilic amorphous polymers

Indomethacin, lacidipine, nifedipine and tolbutamide are poorly soluble in water and may show dissolution-related low oral bioavailability. This study describes the formulation and characterization of these drugs as glass solutions with the amorphous polymers polyvinylpyrrolidone (PVP) and polyvinylpyrrolidone-co-vinyl acetate by melt extrusion. The extrudates were compared with physical mixtures of drug and polymer. X-ray powder diffraction, thermal analysis, infrared spectroscopy, scanning electron microscopy, HPLC, moisture analysis and dissolution were used to examine the physicochemical properties and chemical stability of the glass solutions prepared by melt extrusion at a 1:1 drug/polymer ratio. Depending on the temperature used, melt extrusion produced amorphous glass solutions, with markedly improved dissolution rates compared with crystalline drug. A significant physico-chemical interaction between drug and polymer was found for all extrudates. This interaction was caused by hydrogen bonding (H-bonding) between the carbonyl group of the pyrrole ring of the polymer and a H-donor group of the drug. Indomethacin also showed evidence of H-bonding when physical mixtures of amorphous drug and PVP were prepared. After storage of the extrudates for 4-8 weeks at 25 degrees C/75% relative humidity (RH) only indomethacin/polymer (1:1) extrudate remained totally amorphous. All extrudates remained amorphous when stored at 25 degrees C/< 10% RH. Differences in the physical stability of drug/polymer extrudates may be due to differences in H-bonding between the components.     

Amorphous spray-dried hydroflumethiazide-polyvinylpyrrolidone systems: physiochemical properties

Hydroflumethiazide was spray-dried with polyvinylpyrrolidone (PVP) to produce products containing 0-30% PVP. These systems were amorphous and differed from previously prepared coprecipitates of similar composition. Differential scanning calorimetry (DSC) suggested that at low PVP weight fractions both amorphous drug and an amorphous drug-PVP complex can be present in spray-dried systems. The apparent solubility of hydroflumethiazide in spray-dried products increased with increasing PVP content reaching a plateau value approximately four times that of the pure crystalline drug. The estimated free energy and entropy of the spray-dried drug were greater than that of crystalline drug and also increased with increasing PVP content. Dissolution studies with compressed discs supported the apparent solubility data. The results suggest that amorphous phases having different orders of organization are formed in spray-dried systems with increasing PVP content.