Effect of temperature and moisture on the miscibility of amorphous dispersions of felodipine and poly(vinyl pyrrolidone)

The physical stability of amorphous molecular level solid dispersions will be influenced by the miscibility of the components. The goal of this work was to understand the effects of temperature and relative humidity on the miscibility of a model amorphous solid dispersion. Infrared spectroscopy was used to evaluate drug–polymer hydrogen bonding interactions in amorphous solid dispersions of felodipine and poly(vinyl pyrrolidone) (PVP). Samples were analyzed under stressed conditions: high temperature and high relative humidity. The glass transition temperature (T_g) of select systems was studied using differential scanning calorimetry (DSC). Atomic force microscopy (AFM) and transmission electron microscopy (TEM) were used to further investigate moisture-induced changes in solid dispersions. Felodipine-PVP solid dispersions showed evidence of adhesive hydrogen bonding interactions at all compositions studied. The drug–polymer intermolecular interactions were weakened and/or less numerous on increasing the temperature, but persisted up to the melting temperature of the drug. Changes in the hydrogen bonding interactions were found to be reversible with changes in temperature. In contrast, the introduction of water into amorphous molecular level solid dispersions at room temperature irreversibly disrupted interactions between the drug and the polymer resulting in amorphous-amorphous phase separation followed by crystallization. DSC, AFM, and TEM results provided further evidence for the occurrence of moisture induced immiscibility. In conclusion, it appears that felodipine-PVP solid dispersions are susceptible to moisture-induced immiscibility when stored at a relative humidity ≥75%. In contrast, the solid dispersions remained miscible on heating. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:169–185, 2010     

A Mechanistic Investigation of An Amorphous Pharmaceutical and Its Solid Dispersions,Part II: Molecular Mobility and Activation Thermodynamic Parameters

Purpose. The ability of TSDC to characterize further amorphous materials beyond that possible with DSC was presented in part I (16) of this work. The purpose of part II presented here is to detect and quantitatively characterize time-scales of molecular motions (relaxation times) in amorphous solids at and below the glass transition temperature, to determine distributions of relaxation times associated with different modes of molecular mobility and their temperature dependence, and to determine experimentally the impact upon these parameters of combining the drug with excipients (i.e., solid dispersions at different drug to polymer ratios). The knowledge gleaned may be applied toward a more realistic correlation with physical stability of an amorphous drug within a formulation during storage. Methods. Preparation of amorphous drug and its solid dispersions with PVPK-30 was described in part I (16). Molecular mobility and dynamics of glass transition for these systems were studied using TSDC in the thermal windowing mode. Results. Relaxation maps and thermodynamic activation parameters show the effect of formulating the drug in a solid dispersion on converting the system (drug alone) from one with a wide distribution of motional processes extending over a wide temperature range at and below Tg to one that is homogeneous with very few modes of motion (20% dispersion) that becomes increasingly less homogeneous as the drug load increases (40% dispersion). This is confirmed by the high activation enthalpy (due to extensive intra- and intermolecular interactions) as well as high activation entropy (due to higher extent of freedom) for the drug alone vs. a close to an ideal system (lower enthalpy), with less extent of freedom (low entropy) especially for the 20% dispersion. The polymer PVPK-30 exhibited two distinct modes of motion, one with higher values of activation enthalpies and entropy corresponding to -relaxations, the other with lower values corresponding to -relaxations characterized by local noncooperative motional processes. Conclusions. Using thermal windowing, a distribution of temperature-dependent relaxation times encountered in real systems was obtained as opposed to a single average value routinely acquired by other techniques. Relevant kinetic parameters were obtained and used in mechanistically delineating the effects on molecular mobility of temperature and incorporating the drug in a polymer. This allows for appropriate choices to be made regarding drug loading, storage temperature, and type of polymer that would realistically correlate to physical stability.     

Phase Behavior of Amorphous Molecular Dispersions I: Determination of the Degree and Mechanism of Solid Solubility

PURPOSE: To understand the phase behavior and the degree and mechanism of the solid solubility in amorphous molecular dispersions by the use of thermal analysis. METHODS: Amorphous molecular dispersions of trehalose-dextran and trehalose-PVP were prepared by co-lyophilization. The mixtures were exposed to 23 degrees C, 40 degrees C, and 50 degrees C [75% relative humidity (RH)] and 23 degrees C (69% RH) storage conditions, respectively. Thermal analysis was conducted by modulated differential scanning calorimeter (MDSC). RESULTS: Upon exposure to moisture, two glass transition temperatures (TgS), one for phase-separated amorphous trehalose (Tg1) and the other for polymer-trehalose mixture (Tg2), were observed. With time, Tg2 increased and reached to a plateau (Tg(eq)), whereas Tg1 disappeared. The disappearance of Tg1 was attributed to crystallization of the phase-separated amorphous trehalose. It was observed that Tg(eq) was always less than Tg of pure polymer. The lower Tg(eq) when compared to Tg of pure polymer may be the result of solubility of a fraction of trehalose in the polymers chosen. The miscible fraction of trehalose was estimated to be 12% and 18% wt/wt in dextran at 50 degrees C/75% RH and 23 degrees C/75% RH, respectively, and 10% wt/wt in PVP at 23 degrees C/69% RH. CONCLUSIONS: Mixing behavior of trehalose-dextran and trehalose-PVP dispersions were examined both experimentally and theoretically. A method determining the "extent of molecular miscibility," referred to as "solid solubility," was developed and mechanistically and thermodynamically analyzed. Solid dispersions prepared at trehalose concentrations below the "solid solubility limit" were physically stable even under accelerated stability conditions.     

Understanding the performance of melt-extruded poly(ethylene oxide)-bicalutamide solid dispersions: characterisation of microstructural properties using thermal, spectroscopic and drug release methods

In this article, we have prepared hot-melt-extruded solid dispersions of bicalutamide (BL) using poly(ethylene oxide) (PEO) as a matrix platform. Prior to preparation, miscibility of PEO and BL was assessed using differential scanning calorimetry (DSC). The onset of BL melting was significantly depressed in the presence of PEO, and using Flory-Huggins (FH) theory, we identified a negative value of -3.4, confirming miscibility. Additionally, using FH lattice theory, we estimated the Gibbs free energy of mixing which was shown to be negative, passing through a minimum at a polymer fraction of 0.55. Using these data, solid dispersions at drug-to-polymer ratios of 1:10, 2:10 and 3:10 were prepared via hot-melt extrusion. Using a combination of DSC, powder X-ray diffractometry and scanning electron microscopy, amorphous dispersions of BL were confirmed at the lower two drug loadings. At the 3:10 BL to PEO ratio, crystalline BL was detected. The percent crystallinity of PEO was reduced by approximately 10% in all formulations following extrusion. The increased amorphous content within PEO following extrusion accommodated amorphous BL at drug to polymer loadings up to 2:10; however, the increased amorphous domains with PEO following extrusion were not sufficient to fully accommodate BL at drug-to-polymer ratios of 3:10.     

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     

Drug–Polymer Solubility and Miscibility: Stability Consideration and Practical Challenges in Amorphous Solid Dispersion Development

Drug–polymer solid dispersion has been demonstrated as a feasible approach to formulate poorly water-soluble drugs in the amorphous form, for the enhancement of dissolution rate and bioperformance. The solubility (for crystalline drug) and miscibility (for amorphous drug) in the polymer are directly related to the stabilization of amorphous drug against crystallization. Therefore, it is important for pharmaceutical scientists to rationally assess solubility and miscibility in order to select the optimal formulation (e.g., polymer type, drug loading, etc.) and recommend storage conditions, with respect to maximizing the physical stability. This commentary attempts to discuss the concepts and implications of the drug–polymer solubility and miscibility on the stabilization of solid dispersions, review recent literatures, and propose some practical strategies for the evaluation and development of such systems utilizing a working diagram.     

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.     

Inhibition of albendazole crystallization in poly(vinylpyrrolidone) solid molecular dispersions

The main aim of the study was to investigate the mechanisms of the stabilizing effect of poly(vinylpyrrolidone) (PVP) on amorphous albendazole (ABZ). Solid dispersions of ABZ with PVP polymers and with a copolymer containing poly(vinylacetate) (PVP/VA) were prepared using the solvent casting method. The effects of PVP molecular weight, composition and content on the crystallization of ABZ from the amorphous state were investigated using differential scanning calorimetry. Stability of the amorphous drug with respect to isothermal crystallization was studied at different polymer concentrations and storage temperatures. Solid dispersions were found to be X-ray amorphous and exhibited a single glass transition temperature (Tg). Onset of crystallization and extent of inhibition increased with concentration and molecular weight of the homopolymer. In spite of its having a higher molecular weight, replacement of about 40% of vinylpyrrolidone monomers with vinylacetate groups (as in the copolymer) resulted in reduced inhibition of crystallization. ABZ crystallized from the amorphous state in the absence of polymer even when stored below the Tg. The solvent casting method greatly reduced the requirement for polymer to achieve X-ray amorphous solid dispersions. Such dispersions exhibited a significant increase in induction time and reduction in the rate of crystallization at polymer concentrations as low as 5% and at temperatures as high as 70 degrees C. Factors other than mobility, such as drug-polymer hydrogen bonding' were also found to be involved in crystallization inhibition.     

Use of Surfactants as Plasticizers in Preparing Solid Dispersions of Poorly Soluble API: Stability Testing of Selected Solid Dispersions

Purpose The purpose of the study is to evaluate the effect of surfactant-plasticizers on the physical stability of amorphous drug in polymer matrices formed by hot melt extrusion.Method Solid dispersions of a poorly soluble drug were prepared using PVP-K30, Plasdone-S630, and HPMC-E5 as the polymeric carriers and surfactants as plasticizers. The solid dispersions were produced by hot melt extrusion at temperatures 10°C above and below the glass transition temperature (Tg) of the carrier polymers using a 16 mm-Haake Extruder. The surfactants tested in this study included Tween-80 and Docusate Sodium. The particle size of the extrudate was reduced to have mean of 100–200 micron. The physical stability of the solid dispersions produced was monitored at 30°C/60% for six-months and at 60°C/85% for two-months in open HDPE bottles. Modulated differential scanning calorimetry, polarized light microscopy, powder X-ray diffraction and dissolution testing was performed to assess the physical stability of solid dispersions upon stress testing.Results The dispersions containing HPMC-E5 were observed especially to be susceptible to physical instability under an accelerated stress conditions (60°C/85%RH) of the solid dispersion. About 6% conversion of amorphous drug to crystalline form was observed. Consequently, the system exhibits similar degree of re-crystallization upon addition of the surfactant. However, under 30°C/60%RH condition, the otherwise amorphous Drug-HPMC-E5 system has been destabilized by the addition of the surfactant. This effect is much more reduced in the extruded solid dispersions where polymeric carriers such as Plasdone S-603 and PVP-K30 (in addition to surfactants) are present. Furthermore, the drug release from the solid dispersions was unaffected at the stress conditions reported above.Conclusions Possible reasons for the enhanced stability of the dispersions are due to the surfactants ability to lower the viscosity of the melt, increase the API solubility and homogeneity in the carrier polymer. In contrast, while it is possible for the surfactants to destabilize the system by lowering the Tg and increasing the water uptake, the study confirms that this effect is minimal. By and large, the surfactants appear to be promising plasticizers to produce solid dispersions by hot melt extrusion, in so doing improving dissolution rate without compromising the physical stability of the systems.     

New binary solid dispersion of indomethacin with surfactant polymer: From physical characterization to in vitro dissolution enhancement

This article investigated preparation of solid dispersions containing a poor water-soluble drug, indomethacin (IND), and a new surfactant polymer, polyoxyethylene 32 distearate (POED). Solid dispersions were prepared by the melting method and characterized by DSC, hot-stage microscopy (HSM), X-ray diffraction (XRD) and scanning electron microscopy (SEM). DSC and HSM analyses performed on IND/POED physical mixtures indicated that IND could dissolve in liquid POED. The materials showed complete miscibility at liquid state. Combination of DSC, XRD, and SEM revealed that these materials had limited miscibility at the solid state. Up to 20% w/w IND in POED, we did not detect significant modification of physical properties of the polymer. It supports the formation of a solid solution of IND in solid POED. Above 20% w/w, the solid dispersions presented particular behavior upon heating (recrystallization of IND) and at the solid state (presence of some IND crystallites). Under 3-month storage at 25°C/53% RH, the solid dispersions demonstrated a good stability of the samples. Finally, in vitro dissolution studies showed that IND release was greatly improved (5.5–12 times as fast) by formation of solid dispersion. This enhancement was principally attributed to the high dispersion of IND in POED and to the polymer surfactant properties. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1399–1413, 2010     

The molecular interactions that influence the plasticizer dependent dissolution of acrylic polymer films

Poly(methacrylic acid-methyl methacrylate, 1:2) (Eudragit S) is a commonly used pH-responsive polymer that can facilitate delivery to the ileo-colonic region of the gastrointestinal tract. Different plasticizers have been used to reduce the brittleness of Eudragit S films for the coating of solid dosage forms. To better correlate the dissolution rates of Eudragit S films, we have examined their dielectric response to understand the specific polymer-plasticizer interactions. Solvent cast Eudragit S films were prepared with one of four citrate plasticizers ranging from low to moderate aqueous solubility. Film dissolution was determined using a two-compartment permeation cell. Dielectric properties were measured by thermally stimulated depolarisation currents (TSDC). Secondary relaxations were deconvoluted and identified. The glass transition temperature (T(g)) was measured using TSDC, differential scanning calorimetry (DSC) and dynamic mechanical analysis (DMA). Dissolution of the films was influenced by the solubility and structure of the plasticizers. While no correlation was found among the T(g)'s obtained by TSDC, DSC, and DMA with dissolution time, the low temperature TSDC spectra showed a relationship of the total secondary relaxation area and relaxation of the carboxylic acid functional group with dissolution time. Dielectric secondary relaxations may be a good probe to predict plasticizer influence on dissolution of Eudragit S polymer films.     

Molecular Mobility in Raffinose in the Crystalline Pentahydrate Form and in the Amorphous Anhydrous Form

Purpose The aims of the study are to characterize the slow molecular mobility in solid raffinose in the crystalline pentahydrate form, as well as in the anhydrous amorphous form (T_g = 109°C at 5°C/min), and to analyze the differences and the similarities of the molecular motions in both forms.Methods Thermally stimulated depolarization current (TSDC) is used to isolate the individual modes of motion present in raffinose, in the temperature range between −165 and +60°C. From the experimental output of the TSDC experiments, the kinetic parameters associated with the different relaxational modes of motion were obtained, which allowed a detailed characterization of the distribution of relaxation times of the complex relaxations observed in raffinose. The features of the glass transition relaxation in raffinose were characterized by differential scanning calorimetry (DSC).Results A complex mobility was found in the crystalline form of raffinose. From the analysis of the TSDC data, we conclude that these molecular motions are local and noncooperative. A sub-T_g relaxation, or secondary process, was also detected and analyzed by TSDC in the amorphous phase. It has low activation energy and low degree of cooperativity. The glass transition was studied by DSC. The fragility index (Angell’s scale) of raffinose obtained from DSC data is m = 148.Conclusions TSDC proved to be an adequate technique to study the molecular mobility in the crystalline pentahydrate form of raffinose. In the amorphous form, on the other hand, the secondary relaxation was analyzed by TSDC, but the study of the glass transition relaxation was not possible by this experimental technique as a consequence of conductivity problems. The DSC study of the glass transition indicates that raffinose is an extremely fragile glass former.     

Novel methods for the assessment of miscibility of amorphous drug-polymer dispersions

A typical approach to miscibility analysis of amorphous drug-excipient dispersions involves measuring the glass transition temperature, T_g, using differential scanning calorimetery (DSC). Recently, we discussed two computational methods for the miscibility analysis of amorphous dispersions using X-ray powder diffraction (XRPD). Those methods could be used to qualify an amorphous dispersion as miscible or phase separated, with the implication that miscible dispersions are more stable towards recrystallization. The methods were limited by the need for reference XRPD patterns of both the amorphous drug and excipient. In this work, we propose two additional computational approaches that overcome that limitation and can be used to quantify the degree of miscibility in an amorphous dispersion. The first approach is based on the use of a Pure Curve Resolution Method to extract unknown amorphous references as well as qualify miscibility. The second method, based on Alternate Least Squares, can then be used to quantify the degree of miscibility by determining the nearest neighbor (NN) coordination number for the active pharmaceutical ingredient (API) and excipient. It is proposed that the NN coordination number is related to physical stability. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:3373–3386, 2009     

Evaluation of Inutec SP1 as a new carrier in the formulation of solid dispersions for poorly soluble drugs

Solid dispersions made up of itraconazole and Inutec SP1, a new polymeric surfactant, were prepared by spray drying and hot-stage extrusion. Differential scanning calorimetry (DSC) and X-ray powder diffraction (XRD) were used to evaluate the miscibility of the components of the dispersions, and dissolution experiments were performed in simulated gastric fluid without pepsin (SGFsp) to evaluate the pharmaceutical performance of itraconazole from the solid dispersions. DSC analysis showed that the solid dispersions are phase separated systems made up of glassy and crystalline itraconazole and amorphous Inutec SP1. The amount of crystalline drug substance was higher in the dispersions prepared by hot-stage extrusion and was clearly a function of the drug concentration. Since no crystallinity could be detected by XRD points to the fact that the crystallites formed are very small in size. Despite the presence of glassy and crystalline clusters, the dissolution properties of the solid dispersions were significantly improved in comparison to pure itraconazole (glassy or crystalline) or physical mixtures with Inutec SP1. This study proves the potential of the new polymeric surfactant as a carrier in the formulation of solid dispersions for poorly soluble drugs.     

Physical Properties of Solid Molecular Dispersions of Indomethacin with Poly(vinylpyrrolidone) and Poly(vinylpyrrolidone-co-vinyl-acetate) in Relation to Indomethacin Crystallization

Purpose. To measure solid-state features of amorphous molecular dispersions of indomethacin and various molecular weight grades of poly(vinylpyrrolidone), PVP, and poly(vinylpyrrolidone-co-vinylacetate), PVP/VA, in relation to isothermal crystallization of indomethacin at 30°C Methods. The glass transition temperatures (Tg) of molecular dispersions were measured using differential scanning calorimetry (DSC). FT-IR spectroscopy was used to investigate possible differences in interactions between indomethacin and polymer in the various dispersions. The enthalpy relaxation of 5% w/w and 30% w/w polymer dispersions was determined following various aging times. Quantitative isothermal crystallization studies were carried out with pure indomethacin and 5% w/w polymers in drug as physical mixtures and molecular dispersions. Results. All coprecipitated mixtures exhibited a single glass transition temperature. All polymers interacted with indomethacin in the solid state through hydrogen bonding and in the process eliminated the hydrogen bonding associated with the carboxylic acid dimers of indomethacin. Molecular mobility at 16.5°C below Tg was reduced relative to indomethacin alone, at the 5% w/w and 30% w/w polymer level. No crystallization of indomethacin at 30°C was observed in any of the 5% w/w polymer molecular dispersions over a period of 20 weeks. Indomethacin alone and in physical mixtures with various polymers completely crystallized to the form at this level within 2 weeks. Conclusions. The major basis for crystal inhibition of indomethacin at 30°C at the 5% w/w polymer level in molecular dispersions is not related to polymer molecular weight and to the glass transition temperature, and is more likely related to the ability to hydrogen bond with indomethacin and to inhibit the formation of carboxylic acid dimers that are required for nucleation and growth to the crystal form of indomethacin.     

Physicochemical characterization of solid dispersions of three antiepileptic drugs prepared by solvent evaporation method

We have investigated the solid dispersion and dissolution profiles of three antiepileptic drugs (carbamazepine (CBZ), oxcarbazepine (OXC) and rufinamide (RFN)) with different aqueous solubilities, prepared by the solvent evaporation method. Solid dispersions of the three drugs in hydroxy-propylmethylcellulose (HPMC), with drug:polymer ratios of 1:4, were prepared and characterized by differential scanning calorimetry (DSC), Fourier transformation infrared (FTIR) spectroscopy, X-ray diffraction (XRD) and scanning electron microscopy. The release mechanism was also investigated and the kinetic order of the solid dispersions was evaluated. It appeared that the dissolution behaviour depended on the physicochemical properties of the drug and drug-polymer interactions. DSC thermographs showed amorphous forms for all drugs confirmed by XRD patterns. The FTIR spectra of CBZ and OXC demonstrated drug interactions with HPMC through hydrogen polymer bonds. Thus, solid dispersions of these drugs had an improved dissolution profile. In contrast, solid dispersions of RUF showed modest enhancement of dissolution, suggesting negligible drug-polymer interactions. The different dissolution behaviour is attributed to the extent of interactions between the polymer hydroxyl group and the drug amide groups.     

Prediction of the thermal phase diagram of amorphous solid dispersions by Flory-Huggins theory

Miscibility of drug and polymer is one of the key parameters in amorphous formulation design. The purpose of this work is to provide a theoretical approach to evaluate miscibility between drug and polymer in amorphous solid dispersions. The model system is indomethacin and polyvinylpyrrolidone-vinyl acetate copolymer. The Flory-Huggins (F-H) interaction parameter, χ, of drug and polymer was estimated at different temperatures by two methods: melting point depression of drug in various polymer ratios at the melting temperature, and Hildebrand and Scott solubility parameter calculation at 25°C. The simplified first-order relation between the F-H interaction parameter and temperature was established. This allows the construction of a temperature-composition phase diagram of a two-component amorphous system. The spinodal curve was generated and provides an insight into the thermodynamic stability of an amorphous solid dispersion at various temperatures. The predicted stability of the model system was compared with the experimental data. The merits and deficiency of the proposed approach were fully discussed.     

Phase behaviour analysis of solid dispersions of loperamide and two structurally related compounds with the polymers PVP-K30 and PVP-VA64

The purpose of the present study was to investigate the influence of the structure of a poorly water soluble model drug (loperamide) on the phase behaviour in solid dispersions with PVP-K30. Dispersions with PVP-VA64, a less hydrophilic polymer, were investigated as well in order to study the influence of differences in polymer structure and water content of the samples. The solid dispersions of PVP-K30 or PVP-VA64 with loperamide as well as with two fragments of this molecule were prepared by spray drying. The amount of residual solvents and water was determined with GC and thermogravimetric analysis (TGA). The drug loading of the dispersions was determined using high performance liquid chromatography (HPLC). The solid state properties were evaluated using powder-XRD, IR-spectroscopy and MT-DSC. All mixtures containing loperamide proved to be completely amorphous, whereas the dispersions containing the fragments are only amorphous in case the polymer content is high. The phase diagrams that were constructed clearly show that loperamide exhibits a different behaviour in the solid dispersions than its two building blocks. They also point to the presence of specific intermolecular compound–polymer interactions in the dispersions of one of the fragments with the two polymers. This was confirmed by the IR-results. Despite structural similarities, interactions in dispersions containing loperamide are far less important. In dispersions containing high concentrations of the other fragment, the DSC curves give indications for polymorphism whereas IR and XRD-spectra point towards inclusion of solvent in these samples.     

Influence of Preparation Methods on Solid State Supersaturation of Amorphous Solid Dispersions: A Case Study with Itraconazole and Eudragit E100

Purpose  

The present study aims to determine the drug / polymer miscibility level as a function of the preparation method for an amorphous solid dispersion model system containing itraconazole and eudragit E100. This value was compared to the theoretical crystalline drug solubility in the amorphous polymer and the miscibility of the amorphous drug in the amorphous polymer.