The Activation Energy at T g and the Fragility Index of Indomethacin,Predicted from the Influence of the Heating Rate on the Temperature Position and on the Intensity of Thermally Stimulated Depolarization Current Peak

Purpose. The purpose of this study was to estimate the activation energy at the glass transition temperature (and the fragility index) of amorphous indomethacin from the influence of heating rate on the features of the relaxation peaks obtained by thermally stimulated depolarization currents (TSDC) and to compare the obtained results with those obtained by other procedures based on TSDC data. Methods. The glass transition temperature region of amorphous indomethacin was characterized at different heating rates by TSDC in a way similar to that used to determine the kinetics of the glass transition relaxation by differential scanning calorimetry. The features of a thermal sampled TSDC peak, namely the temperature location and the intensity, depend on the heating rate. Results. The activation energy for structural relaxation (directly related to glass fragility) was estimated from the heating rate dependence of the TSDC peak location, T _m, and of the maximum intensity of the TSDC peak, I(T _m). Conclusions. The methods for determining the activation energy for structural relaxation and fragility of indomethacin from TSDC data obtained with different heating rates were compared with other procedures previously proposed. TSDC, which is not a very familiar technique in the community of pharmaceutical scientists, proved to be a very convenient technique to study molecular mobility and to determine the fragility index in glass-forming systems. The value of 60 appears as a reasonable value of the fragility index of indomethacin.     

A Mechanistic Investigation of an Amorphous Pharmaceutical and Its Solid Dispersions,Part I: A Comparative Analysis by Thermally Stimulated Depolarization Current and Differential Scanning Calorimetry

PURPOSE: To explore using thermally stimulated depolarization current (TSDC), in comparison to differential scanning calorimetry (DSC), for the characterization of molecular mobility of an amorphous pharmaceutical new chemical entity (LAB687), an amorphous polymer (PVPK-30), and their combination as solid dispersions at different % drug loadings. METHODS: Amorphous drug was prepared by quenching from the melt. Solid dispersions containing 10-60% of drug in polymer were prepared by solvent evaporation method. Glass transition temperatures (Tg) were determined by DSC and TSDC. RESULTS: In comparison to a single T. obtained from DSC for the drug substance, TSDC shows two overlapping relaxations. Both peaks correspond to a-relaxations that are associated with the glass transition, with the second peak corresponding to the rigid fraction that is difficult to be detected by DSC because it is associated with only small changes in heat capacity. Two overlapping relaxations were also observed for the polymer vs. one Tg by DSC. The lower temperature relaxation is believed to be a beta-relaxation, whereas the higher temperature transition corresponds to an alpha-relaxation. For the solid dispersions, one single peak was obtained for each of the 20% and 30% dispersions in excellent agreement with the DSC results. However, at the 40% drug load, a small shoulder was observed by TSDC at the low temperature of the main peak. This shoulder becomes more pronounced and overlaps with the main peak as the drug load increases to 50% and 60%. Agreement between the Tg values calculated by the Gordon-Taylor equation and the DSC and TSDC experimental data, especially for the 20% and 30% drug loading, indicate ideal miscibility. At higher drug loads, only by TSDC was it possible to detect the saturation level of the drug in the polymer. CONCLUSIONS: TSDC proved to be very sensitive in detecting small reorientational motions in solids and in separating overlapping events with only slight differences in molecular motion exhibited as broad events in DSC. This allowed for detection of the rigid fraction of the amorphous drug, the sub-glass transition beta- relaxation in the polymer, and the limit of miscibility between the drug and the polymer in the solid dispersions.     

Spectroscopic Characterization of Interactions Between PVP and Indomethacin in Amorphous Molecular Dispersions

Purpose. To study the molecular structure of indomethacin-PVP amorphous solid dispersions and identify any specific interactions between the components using vibrational spectroscopy. Methods. Solid dispersions of PVP and indomethacin were prepared using a solvent evaporation technique and IR and FT-Raman spectra were obtained. Results. A comparison of the carbonyl stretching region of indomethacin, known to form carboxylic acid dimers, with that of amorphous indomethacin indicated that the amorphous phase exists predominantly as dimers. The hydrogen bonding of indomethacin is not as dimers. Addition of PVP to amorphous indomethacin increased the intensity of the infrared band assigned to non-hydrogen bonded carbonyl. Con-comitantly, the PVP carbonyl stretch appeared at a lower wavenumber indicating hydrogen bonding. Model solvent systems aided spectral interpretation. The magnitude of the spectral changes were comparable for an indomethacin-PVP solid dispersion and a solution of indomethacin in methylpyrrolidone at the same weight percent. Conclusions. Indomethacin interacts with PVP in solid dispersions through hydrogen bonds formed between the drug hydroxyl and polymer carbonyl resulting in disruption of indomethacin dimers. PVP may influence the crystallisation kinetics by preventing the self association of indomethacin molecules. The similarity of results for solid dispersions and solutions emphasises the 'solution' nature of this binary amorphous state.     

Molecular Mobility and Fragility in Indomethacin: A Thermally Stimulated Depolarization Current Study

Purpose. To show that thermally stimulated depolarization currents (TSDC), which is a dielectric experimental technique relatively unknown in the pharmaceutical scientists community, is a powerful technique to study molecular mobility in pharmaceutical solids, below their glass transition temperature (T_g). Indomethacin (T_g = 42°C) is used as a model compound. Methods. TSDC is used to isolate the individual modes of motion present in indomethacin, in the temperature range between –165°C 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 indomethacin. Results. Two different relaxational processes were detected and characterized: the glass transition relaxation, or -process, and a sub-T_g relaxation, or secondary process. The lower temperature secondary process presents a very low intensity, a very low activation energy, and a very low degree of cooperativity. The fragility index (Angell's scale) of indomethacin obtained from TSDC data is m = 64, which can be compared with other values reported in the literature and obtained from other experimental techniques. Conclusions. TSDC data indicate that indomethacin is a relatively strong glass former (fragility similar to glycerol but lower than sorbitol, trehalose, and sucrose). The high-resolution power of the TSDC technique is illustrated by the fact that it detected and characterized the secondary relaxation in indomethacin, which was not possible by other techniques.     

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。     

Determination of the Viscosity of an Amorphous Drug Using Thermomechanical Analysis (TMA)

Purpose. To evaluate thermomechanical analysis (TMA) as a technique for determining the viscosity of amorphous pharmaceutical materials. This property of amorphous drugs and excipients is related to their average rate of molecular mobility and thus to their physical and chemical stability. Methods. Indomethacin was selected as a model amorphous drug whose viscosity has previously been reported in the literature. A Seiko TMA 120C thermomechanical analyzer was utilized in isothermal penetration mode to determine the viscosity of the amorphous drug over the maximum possible range of temperatures. Results. Using a cylindrical penetration geometry it was possible to accurately determine the viscosity of amorphous indomethacin samples by TMA over the temperature range from 35 to 75°C. The results were consistent with those reported in the literature using a controlled strain rheometer over the range 44–75°C. The limiting lower experimental temperature for the TMA technique was extended to significantly below the calorimetric glass transition temperature (T_g 42°C), thus allowing a direct experimental determination of the viscosity at T_g to be made. Conclusions. Thermomechanical analysis can be used to accurately determine the viscosity of amorphous pharmaceutical materials at temperatures near and above their calorimetric glass transition temperatures.     

Freeze-Concentration Separates Proteins and Polymer Excipients Into Different Amorphous Phases

Purpose. To study the miscibility of proteins and polymer excipients in frozen solutions and freeze-dried solids as protein formulation models. Methods. Thermal profiles of frozen solutions and freeze-dried solids containing various proteins (lysozyme, ovalbumin, BSA), nonionic polymers (Ficoll, polyvinylpyrrolidone [PVP]), and salts were analyzed by differential scanning calorimetry (DSC). The polymer miscibility was determined from the glass transition temperature of maximally freeze-concentrated solute (T_g) and the glass transition temperature of freeze-dried solid (T_g). Results. Frozen Ficoll or PVP 40k solutions showed T_g at –22°C, while protein solutions did not show an apparent T_g. All the protein and nonionic polymer combinations (5% w/w, each) were miscible in frozen solutions and presented single T_gs that rose with increases in the protein ratio. Various salts concentration-dependently lowered the single T_gs of the proteins and Ficoll combinations maintaining the mixed amorphous phase. In contrast, some salts induced the separation of the proteins and PVP combinations into protein-rich and PVP-rich phases among ice crystals. The T_gs of these polymer combinations were jump-shifted to PVP's intrinsic T_g at certain salt concentrations. Freeze-dried solids showed varied polymer miscibilities identical to those in frozen solutions. Conclusions. Freeze-concentration separates some combinations of proteins and nonionic polymers into different amorphous phases in a frozen solution. Controlling the polymer miscibility is important in designing protein formulations.     

Preparation and Characterization of Nanofibers Containing Amorphous Drug Dispersions Generated by Electrostatic Spinning

Purpose. We assessed the application of water-soluble polymer-based nanofibers prepared by electrostatic spinning as a means of altering the dissolution rate of the poorly water-soluble drug, itraconazole. Methods. Organic solvent-based solutions of itraconazole/HPMC mixtures were electrostatically spun at 16 and 24 kV. The formed nanofibers were collected as a non-woven fabric. The samples were analyzed by scanning electron microscopy, differential scanning calorimetry, and dissolution rate. Results. Scanning electron microscopy showed fiber diameters of 1-4 m and 300-500 nm depending on the applied voltage. Differential scanning calorimetry measurements found that the melting endotherm for itraconazole was not present, suggesting the formation of an amorphous solid dispersion or solution. Dissolution studies assessed several presentations including direct addition of the non-woven fabrics to the dissolution vessels, folding weighed samples of the materials into hard gelatin capsules and placing folded material into a sinker. Controls included a physical mixture as well as solvent cast and melt extruded samples. Electrospun samples dissolved completely over time with the rate of dissolution depending on the formulation presentation and drug to polymer ratio. The physical mixture did not appreciably dissolve in these conditions. Conclusions. The application of electrostatic spinning to pharmaceutical applications resulted in dosage forms with useful and controllable dissolution properties.     

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.     

Analysis of the Initial Burst of Drug Release Coupled with Polymer Surface Degradation

Purpose. Local pH effect on the release of a model pH-inert hydrophobic drug coupled with polymer degradation is described at the induction phase of biodegradable polymer erosion for better understanding the nature of initial burst of a drug. Methods. Using a novel approach with time-of-flight secondary ion mass spectrometry, both surface concentration of Ph₃N and degradation kinetics of PLLA are simultaneously and independently determined from a model Ph₃N/PLLA (20:80 wt%) blend matrix (t 0.4 m on 1.0 cm²). In vitro hydrolysis of the model blend matrix is investigated for short-term periods (<24 h) at physiologic pH and temperature and compared to basic pH. Results. The rate of PLLA degradation is accelerated by a factor of 3 when using basic pH in vitro, but the rate of Ph₃N accumulation at the surface is accelerated by a factor of 6. Conclusions. A new quantitative method has been developed to examine the earliest stages of polymer degradation and drug release. It was applied to a model system that could not be examined by traditional in vitro methods. For the model system studied the release of a low molecular weight hydrophobic drug at the induction phase of polymer erosion is related to but not singularly dependent on degradation kinetics.     

A Biodegradable Injectable Implant Sustains Systemic and Ocular Delivery of an Aldose Reductase Inhibitor and Ameliorates Biochemical Changes in a Galactose-Fed Rat Model for Diabetic Complications

Purpose. To fabricate and characterize in vitro and in vivo performance of a sustained release biodegradable implant for N-4-(benzoylaminophenylsulfonyl glycine) (BAPSG), a novel aldose reductase inhibitor. Methods. The ability of BAPSG to inhibit aldose reductase activity and glucose-induced vascular endothelial growth factor (VEGF) expression was assessed in a retinal pigment epithelial cell line (ARPE-19). A poly (DL-lactic-co-glycolic acid) implant containing 50% w/w BAPSG was fabricated and characterized for drug loading, in vitro drug release, and the thermal behavior of the drug and the polymer. Implants were injected subcutaneously into a galactose-fed diabetic rat model and cataract scores, plasma and tissue drug levels, galactitol levels in the lens and the retina, glutathione levels in the plasma, lens, cornea and retina and VEGF expression in the retina were determined on or until 18 days. Results. BAPSG inhibited aldose reductase activity and reduced VEGF expression in ARPE-19 cells. Implants (1 × 4 mm), with a loading efficiency of 106 7% for BAPSG, were fabricated. Upon implant fabrication, while the glass transition temperature of the polymer decreased, the melting point of the drug was not affected. In vivo drug release correlated well with in vitro release, with 44% drug release occurring in vivo by the end of 18 days. The implant reduced galactitol accumulation, glutathione depletion, cataract scores, and VEGF expression in galactose-fed rats. Conclusions. An injectable biodegradable implant of BAPSG sustained drug release in vitro and in vivo, and reduced galactitol accumulation, glutathione depletion, cataract scores, and VEGF expression in galactose-fed rats.     

PLG Microsphere Size Controls Drug Release Rate Through Several Competing Factors

Purpose. Although the rate of drug release from poly(D,L-lactide-co-glycolide) (PLG) microspheres is often modulated by changing fabrication conditions or materials, the specific factors directly controlling the release profiles are often unclear. We have fabricated uniform rhodamine- and piroxicam-containing microspheres, 10 to 100 m in diameter, to better understand how microsphere size controls drug release. Methods. Drug distribution within the microspheres was examined using confocal fluorescence microscopy. The rate of polymer degradation was determined as the change in molecular weight, measured by gel permeation chromatography, during in vitro degradation experiments. Further, changes in the surface and interior morphology of the particles during in vitro degradation were investigated by scanning electron microscopy. Results. Microsphere size greatly affected drug distribution. Small (10-m) microspheres showed an essentially uniform drug distribution. Larger (100-m) microspheres showed redistribution of drug to specific regions of the microspheres. Rhodamine partitioned to the surface and piroxicam partitioned to the interior of large PLG microspheres. Further, the rate of polymer degradation increased with microsphere size, possibly the result of a more acidic interior caused by increased accumulation of hydrolyzed polymer products in larger particles. Finally, larger microspheres developed a more porous interior structure during the drug release. Conclusions. Microsphere size affects drug release not only through changes in diffusion rates but also through secondary effects including drug distribution in the particle, polymer degradation rate, and microsphere erosion rates.     

Molecular Motions in Sucrose-PVP and Sucrose-Sorbitol Dispersions—II. Implications of Annealing on Secondary Relaxations

Purpose

To determine the effect of annealing on the two secondary relaxations in amorphous sucrose and in sucrose solid dispersions.

Methods

Sucrose was co-lyophilized with either PVP or sorbitol, annealed for different time periods and analyzed by dielectric spectroscopy.

Results

In an earlier investigation, we had documented the effect of PVP and sorbitol on the primary and the two secondary relaxations in amorphous sucrose solid dispersions (1). Here we investigated the effect of annealing on local motions, both in amorphous sucrose and in the dispersions. The average relaxation time of the local motion (irrespective of origin) in sucrose, decreased upon annealing. However, the heterogeneity in relaxation time distribution as well as the dielectric strength decreased only for β₁- (the slower relaxation) but not for β₂-relaxations. The effect of annealing on β₂-relaxation times was neutralized by sorbitol while PVP negated the effect of annealing on both β₁- and β₂-relaxations.

Conclusions

An increase in local mobility of sucrose brought about by annealing could be negated with an additive.     

A Pragmatic Test of a Simple Calorimetric Method for Determining the Fragility of Some Amorphous Pharmaceutical Materials

Purpose. To evaluate a simple calorimetric method for estimating the fragility of amorphous pharmaceutical materials from the width of the glass transition region. Methods. The glass transition temperature regions of eleven amorphous pharmaceutical materials were characterized at six different heating and cooling rates by differential scanning calorimetry (DSC). Results. Activation energies for structural relaxation (which are directly related to glass fragility) were estimated from the scan rate dependence of the glass transition temperature, and correlations between the glass transition widths and the activation energies were examined. The expected correlations were observed, and the exact nature of the relationship varied according to the type of material under consideration. Conclusions. The proposed method of determining the fragility of amorphous materials from the results of simple DSC experiments has some utility, although "calibration of the method for each type of materials is necessary. Further work is required to establish the nature of the relationships for a broad range of amorphous pharmaceutical materials.     

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

     

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.     

Prediction of Glass Transition Temperature of Freeze-Dried Formulations by Molecular Dynamics Simulation

Purpose. To examine whether the glass transition temperature (T_g) of freeze-dried formulations containing polymer excipients can be accurately predicted by molecular dynamics simulation using software currently available on the market. Molecular dynamics simulations were carried out for isomaltodecaose, a fragment of dextran, and -glucose, the repeated unit of dextran, in the presence or absence of water molecules. Estimated values of T_g were compared with experimental values obtained by differential scanning calorimetry (DSC). Methods. Isothermal-isobaric molecular dynamics simulations (NPTMD) and isothermal molecular dynamics simulations at a constant volume (NVTMD) were carried out using the software package DISCOVER (Material Studio) with the Polymer Consortium Force Field. Mean-squared displacement and radial distribution function were calculated. Results. NVTMD using the values of density obtained by NPTMD provided the diffusivity of glucose-ring oxygen and water oxygen in amorphous -glucose and isomaltodecaose, which exhibited a discontinuity in temperature dependence due to glass transition. T_g was estimated to be approximately 400K and 500K for pure amorphous -glucose and isomaltodecaose, respectively, and in the presence of one water molecule per glucose unit, T_g was 340K and 360K, respectively. Estimated T_g values were higher than experimentally determined values because of the very fast cooling rates in the simulations. However, decreases in T_g on hydration and increases in T_g associated with larger fragment size could be demonstrated. Conclusions. The results indicate that molecular dynamics simulation is a useful method for investigating the effects of hydration and molecular weight on the T_g of lyophilized formulations containing polymer excipients, although the relationship between cooling rates and T_g must first be elucidated to predict T_g vales observed by DSC measurement. January 16     

Enthalpy Relaxation in Binary Amorphous Mixtures Containing Sucrose

Purpose. To compare the enthalpy relaxation of amorphous sucrose and co-lyophilized sucrose-additive mixtures near the calorimetric glass transition temperature, so as to measure the effects of additives on the molecular mobility of sucrose. Methods. Amorphous sucrose and sucrose-additive mixtures, containing poly(vinylpyrrolidone) (PVP), poly(vinylpyrrolidone-co-vinyl-acetate) (PVP/VA) dextran or trehalose, were prepared by lyophilization. Differential scanning calorimetry (DSC) was used to determine the area of the enthalpy recovery endotherm following aging times of up to 750 hours for the various systems. This technique was also used to compare the enthalpy relaxation of a physical mixture of amorphous sucrose and PVP. Results. Relative to sucrose alone, the enthalpy relaxation of co-lyophilized sucrose-additive mixtures was reduced when aged for the same length of time at a comparable degree of undercooling in the order: dextran PVP > PVP/VA > trehalose. Calculated estimates of the total enthalpy change required for sucrose and the mixtures to relax to an equilibrium supercooled liquid state (H) were essentially the same and were in agreement with enthalpy changes measured at longer aging times (750 hours). Conclusions. The observed decrease in the enthalpy relaxation of the mixtures relative to sucrose alone indicates that the mobility of sucrose is reduced by the presence of additives having a T_g that is greater than that of sucrose. Comparison with a physically mixed amorphous system revealed no such effects on sucrose. The formation of a molecular dispersion of sucrose with a second component, present at a level as low as 10%, thus reduces the mobility of sucrose below T_g, most likely due to the coupling of the molecular motions of sucrose to those of the additive through molecular interactions.     

Coupling of Naltrexone to Biodegradable Poly(α-Amino Acids)

The narcotic antagonist naltrexone (I) was modified at the 3 and 14 hydroxyl positions and covalently coupled to a biodegradable poly(-amino acid) backbone through a labile bond. Selective acetylation of I with acetic anhydride gave naltrexone-3-acetate (II), which was subsequently succinoylated to naltrexone-3-acetate-14-hemisuccinate (III) with succinic anhydride. The polymeric backbone chosen for initial coupling experiments was poly-N ⁵-(3-hydroxypropyl)-L-glutamine (PHPG). The side-chain hydroxyl functionality permitted covalent bonding of III through an ester linkage. Hydrolysis of covalently bound drug to give naltrexone or its derivatives (II and III) should be much slower than diffusion of drug through the polymer matrix. While hydrolysis of naltrexone from the polymer side chain is first order, release of drug from the matrix can be zero order due to the geometry of the device and the physical and chemical interactions between naltrexone and the polymer matrix. In vitro studies of PHPG–naltrexone conjugate in disk form did not show constant release because of the hydrophilic nature of the polymer backbone and the changing local chemical environment upon hydrolysis of drug–polymer linkages. The conjugated system was made more hydrophobic by coupling drug to copolymers of hydroxypropyl-L-glutamine (HPG) and L-leucine. Conjugates of III coupled with copoly(HPG-70/Leu-30) demonstrated a nearly constant, but slightly declining release rate of naltrexone and its derivatives for 28 days in vitro.     

Correlation of Inhibitory Effects of Polymers on Indomethacin Precipitation in Solution and Amorphous Solid Crystallization Based on Molecular Interaction

Purpose

To correlate the polymer’s degree of precipitation inhibition of indomethacin in solution to the amorphous stabilization in solid state.

Methods

Precipitation of indomethacin (IMC) in presence of polymers was continuously monitored by a UV spectrophotometer. Precipitates were characterized by PXRD, IR and SEM. Solid dispersions with different polymer to drug ratios were prepared using solvent evaporation. Crystallization of the solid dispersion was monitored using PXRD. Modulated differential scanning calorimetry (MDSC), IR, Raman and solid state NMR were used to explore the possible interactions between IMC and polymers.

Results

PVP K90, HPMC and Eudragit E100 showed precipitation inhibitory effects in solution whereas Eudragit L100, Eudragit S100 and PEG 8000 showed no effect on IMC precipitation. The rank order of precipitation inhibitory effect on IMC was found to be PVP K90?>?Eudragit E100?>?HPMC. In the solid state, polymers showing precipitation inhibitory effect also exhibited amorphous stabilization of IMC with the same rank order of effectiveness. IR, Raman and solid state NMR studies showed that rank order of crystallization inhibition correlates with strength of molecular interaction between IMC and polymers.

Conclusions

Correlation is observed in the polymers ability to inhibit precipitation in solution and amorphous stabilization in the solid state for IMC and can be explained by the strength of drug polymer interactions.