Molecular Mobility of Protein in Lyophilized Formulations Linked to the Molecular Mobility of Polymer Excipients,as Determined by High Resolution 13C Solid-State NMR

Purpose. The mobility of protein molecules in lyophilized protein formulations was compared with that of excipient molecules based on the spin-lattice relaxation time (T₁) of each molecule determined by high resolution ¹³C solid-state NMR. The relationship between molecular mobility and protein stability is discussed. Methods. Protein aggregation of lyophilized bovine serum --globulin (BGG) formulation containing dextran was measured by size exclusion chromatography. The T₁ of the BGG carbonyl carbon and dextran methin carbon in the formulation was determined by high resolution ¹³C NMR, and subsequently used to calculate the correlation time (_C) of each carbon. The spin-spin relaxation time (T₂) of BGG and dextran protons was measured by pulsed NMR spectrometry, and the critical temperature of appearance of Lorentzian relaxation due to liquid BGG and dextran protons (T_mc) was determined. Results. The _C of dextran methin carbon in BGG-dextran formulations exhibited a linear temperature dependence according to the Adam-Gibbs-Vogel equation at lower temperatures, and a nonlinear temperature dependence described by the Vogel-Tamman-Fulcher equation at higher temperatures. The temperature at which molecular motion of dextran changed was consistent with the T_mc. The _C of BGG carbonyl carbon exhibited a similar temperature dependence to the _C of the dextran methin carbon and substantially decreased at temperatures above T_mc in the presence of dextran. The temperature dependence of BGG aggregation could be described by the Williams-Landel-Ferry equation even at temperatures 20°C lower than T_mc. Conclusions. High resolution ¹³C solid-state NMR indicated that the molecular motion of BGG was enhanced above T_mc in association with the increased global segmental motion of dextran molecules.     

Temperature Dependence of Bimolecular Reactions Associated with Molecular Mobility in Lyophilized Formulations

Purpose. We studied the temperature dependence of acetyltransfer between aspirin and sulfadiazine, a bimolecular reaction, inlyophilized formulations at temperatures near the glass transitiontemperature (T_g) and NMR relaxation-based critical mobilitytemperature (T_mc), to further understand the effect of molecularmobility on chemical degradation rates in solid pharmaceutical formulations.The temperature dependence of the hydrolysis rates of aspirin andcephalothin in lyophilized formulations was also studied as a model ofbimolecular reactions in which water is a reactant. Methods. Degradation of lyophilized aspirin-sulfadiazineformulations containing dextran and various amounts of water at temperaturesranging from 1°C to 80°C was analyzed by HPLC. The degradation ofcephalothin in lyophilized formulations containing dextran andmethylcellulose was also analyzed at temperatures ranging from 10°C to70°C. Results. Acetyl transfer in lyophilizedasprin—sulfadiazine formulations containing dextran exhibited atemperature dependence with a distinct break around T_mc, whichmay be ascribed to a change in the translational mobility of aspirin andsulfadiazine molecules. The hydrolysis of aspirin and cephalothin inlyophilized formulations, which is also a bimolecular reaction, did not showa distinct break, suggesting that water diffusion is not rate-limiting. Conclusions. The diffusion barrier of water molecules inlyophilized formulations appears to be smaller than the activational barrierof the hydrolysis of aspirin and cephalothin based on the results of thisstudy that the temperature dependence of the hydrolysis rate is almostlinear regardless of T_mc and T_g. On the other hand,the diffusion barrier of aspirin and sulfadiazine molecules appears to becomparable to the activational barrier of the acetyl transfer reactionbetween these com pounds, resulting in nonlinear temperature dependence.     

A Quantitative Assessment of the Significance of Molecular Mobility as a Determinant for the Stability of Lyophilized Insulin Formulations

Purpose The purpose was to explore a method for quantitatively assessing the contribution of molecular mobility to the chemical reactivity of amorphous solids. Degradation of insulin in lyophilized formulations containing trehalose and poly(vinylpyrrolidone)(PVP) was chosen as a model system, and the temperature- and glass transition temperature (T_g)-dependence of the degradation rate was analyzed to obtain the relative contributions of molecular mobility and that of the chemical activational barrier reflected in the energy of activation.Methods Insulin degradation and dimerization in lyophilized trehalose and PVP formulations were monitored at various relative humidities (6–60% RH) and temperatures (10–60°C) by reverse-phase high-performance liquid chromatography (HPLC) and high-performance size-exclusion chromatography (HP-SEC), respectively. The T_g and fragility parameter of the lyophilized insulin formulations were determined by differential scanning calorimetry (DSC).Results Insulin degradation in the initial stage was describable with first-order kinetics for both of the trehalose and PVP formulations. The temperature- and T_g-dependence of the degradation rate indicated that the reactivity of insulin in the trehalose formulation is affected by molecular mobility at low humidity (12% RH), such that the ratio of the observed rate constant (k′) to the rate constant governed only by the activational barrier (k) was 0.051 at the T_g. At higher humidities, in contrast, the value of k′/k was much higher (0.914, 0.978, and 0.994 for 23% RH, 33% RH, and 43% RH, respectively), indicating that insulin degradation rate is determined predominantly by the activational barrier. For insulin degradation in the PVP formulation at temperatures below T_g, the contribution of molecular mobility to the degradation rate appeared to be negligible, as the extrapolated value of t₉₀ at the T_g exhibited a large difference between the formulations with differing T_g values (because of differing water contents).Conclusions The reactivity of insulin in the trehalose and PVP formulations can be described by an equation including factors reflecting the activational barrier (activation energy and frequency coefficient) and factors reflecting the molecular mobility (T_g, fragility parameter and a constant representing the relationship between the molecular mobility and the reaction rate). Thus, analysis of temperature dependence based on the proposed equation allows quantitative assessment of the significance of molecular mobility as a factor affecting chemical reactivity.     

Usefulness of the Kohlrausch-Williams-Watts Stretched Exponential Function to Describe Protein Aggregation in Lyophilized Formulations and the Temperature Dependence Near the Glass Transition Temperature

Purpose. We studied the feasibility of using the Kohlrausch-Williams-Watts stretched exponential function (KWW equation) to describe protein aggregation in lyophilized formulations during storage. Parameters representing mean aggregation time (_a) and stretched exponential constant (_a) were calculated according to the KWW equation by assuming that the time required for protein molecules to aggregate () varies because of the fact that protein aggregation occurs at a rate that depends on the degree of protein deformation resulting from stresses created during freeze-drying. The temperature dependence of the parameters near the glass transition temperature was examined to discuss the possibility of predicting protein aggregation by accelerated testing. Methods. Protein aggregation in lyophilized bovine serum -globulin (BGG) formulations containing dextran or methylcellulose, at temperatures ranging from 10 to 80°C, was followed by size-exclusion chromatography. Results. Non-exponential BGG aggregation in lyophilized formulations could be described by the KWW equation. The _a and _a parameters changed abruptly around the NMR relaxation-based critical mobility temperature for formulations containing dextran and methylcellulose. In the glassy state, in contrast, the _a parameter of these formulations exhibited continuous temperature dependence. The parameter , as calculated from _a and _a, reflected differences in values between the two excipients. Conclusions. The results indicate that the parameter _a is reflective of physical changes wihtin lyophilized formulations. Within the temperature range, during which no abrupt changes in _a were observed, knowledge regarding the _aand _a parameters allows the rate of protein aggregation to be predicted. The parameter was found to be useful in comparing the protein aggregation behavior of formulations having different _a and _a values.     

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     

The Relationship Between Protein Aggregation and Molecular Mobility Below the Glass Transition Temperature of Lyophilized Formulations Containing a Monoclonal Antibody

Purpose. To find out if the physical instability of a lyophilized dosage form is related to molecular mobility below the glass transition temperature. Further, to explore if the stability data generated at temperatures below the glass transition temperature can be used to predict the stability of a lyophilized solid under recommended storage conditions. Methods. The temperature dependence of relaxation time constant, , was obtained for sucrose and trehalose formulations of the monoclonal antibody (5 mg protein/vial) from enthalpy relaxation studies using differential scanning calorimetry. The non-exponentiality parameter, , in the relaxation behavior was also obtained using dielectric relaxation spectroscopy. Results. For both sucrose and trehalose formulations, the variation in with temperature could be fitted Vogel-Tammann-Fulcher (VTF) equation. The two formulations exhibited difference sensitivities to temperature. Sucrose formulation was more fragile and exhibited a stronger non-Arrhenius behavior compared to trehalose formulation below glass transition. Both formulations exhibited <2% aggregation at t values <10, where t is the time of storage. Conclusions. Since the relaxation times for sucrose and trehalose formulations at 5°C are on the order of 10⁸ and 10⁶ hrs, it is likely that both formulations would undergo very little (<2%) aggregation in a practical time scale under refrigerated conditions.     

Molecular Mobility of Amorphous Pharmaceutical Solids Below Their Glass Transition Temperatures

Purpose. To measure the molecular mobility of amorphous pharmaceutical solids below their glass transition temperatures (Tg), using indomethacin, poly (vinyl pyrrolidone) (PVP) and sucrose as model compounds. Methods. Differential scanning calorimetry (DSC) was used to measure enthalpic relaxation of the amorphous samples after storage at temperatures 16-47 K below Tg for various time periods. The measured enthalpy changes were used to calculate molecular relaxation time parameters. Analogous changes in specimen dimensions were measured for PVP films using thermomechanical analysis. Results. For all the model materials it was necessary to cool to at least 50 K below the experimental Tg before the molecular motions detected by DSC could be considered to be negligible over the lifetime of a typical pharmaceutical product. In each case the temperature dependence of the molecular motions below Tg was less than that typically reported above Tg and was rapidly changing. Conclusions. In the temperature range studied the model amorphous solids were in a transition zone between regions of very high molecular mobility above Tg and very low molecular mobility much further below Tg. In general glassy pharmaceutical solids should be expected to experience significant molecular mobility at temperatures up to fifty degrees below their glass transition temperature.     

Predictions of Onset of Crystallization from Experimental Relaxation Times I-Correlation of Molecular Mobility from Temperatures Above the Glass Transition to Temperatures Below the Glass Transition

Purpose Predicting onsets of crystallization at temperatures below T _g, from data above T _g, would require that the correlation between crystallization onset and mobility is same above and below T _g, and the techniques being used to measure mobility above and below T _g are measuring essentially the same kind of mobility. The aim of this work is to determine if the relaxation times obtained using different techniques (DSC, TAM) below T _g correlate with relaxation time obtained above T _g using dielectric spectroscopy.Methods Model compounds for this work were chosen based on their varied ΔH _f, ΔC _p(T _g) and H-bonding in crystalline state vs. amorphous state. Relaxation times above T _g were determined by the simultaneous fit of real and imaginary permittivity to the Cole-Davidson model. Tau and beta below T _g were determined using isothermal microcalorimetry (TAM) or MDSC. MDSC was used to calculate Kauzmann temperature and strength of the glass using established relationships.Results Indomethacin, nifedipine and flopropione showed Arrhenius temperature dependence throughout the entire temperature range and extrapolation of τ ^β measured above T _g by dielectric relaxation agreed with τ ^β measured below T _g by TAM/MDSC. Ketoconazole, however, showed the expected VTF behavior. For at least two compounds compared (indomethacin and ketoconazole), relaxation times measured by TAM and MDSC did not agree, with TAM giving significantly lower values of τ ^β , but TAM and MDSC relaxation times appeared to extrapolate to a common value at T _g.Conclusions It was found that, for all cases studied, relaxation time constants determined above and below T _g did appear to extrapolate to the same value around T _g indicating that molecular mobility measured above and below T _g using different techniques is highly correlated.     

Effect of Glass Transition Temperature on the Stability of Lyophilized Formulations Containing a Chimeric Therapeutic Monoclonal Antibody

Purpose. The purpose of this study is to highlight the importance of knowing the glass transition temperature, T_g, of a lyophilized amorphous solid composed primarily of a sugar and a protein in the interpretation of accelerated stability data. Methods. Glass transition temperatures were measured using DSC and dielectric relaxation spectroscopy. Aggregation of protein in the solid state was monitored using size-exclusion chromatography. Results. Sucrose formulation (T_g ~ 59°C) when stored at 60°C was found to undergo significant aggregation, while the trehalose formulation (T_g ~ 80°C) was stable at 60°C. The instability observed with sucrose formulation at 60°C can be attributed to its T_g (~59°C) being close to the testing temperature. Increase in the protein/sugar ratio was found to increase the T_gs of the formulations containing sucrose or trehalose, but to different degrees. Conclusions. Since the formulations exist in glassy state during their shelf-life, accelerated stability data generated in the glassy state (40°C) is perhaps a better predictor of the relative stability of formulations than the data generated at a higher temperature (60°C) where one formulation is in the glassy state while the other is near or above its T_g.     

The Molecular Mobility of Supercooled Amorphous Indomethacin as a Function of Temperature and Relative Humidity

Purpose. To determine the relaxation times of supercooled indomethacin as a function of temperature and relative humidity above Tg, and to analyze the results in the context of being able to predict such behavior at various storage conditions. Methods. Dielectric relaxation times were measured in the frequency domain (12 to 10⁵ Hz) for amorphous indomethacin equilibrated at 0, 56, and 83% relative humidity. The heating rate dependence of Tg for dry supercooled indomethacin was measured with differential scanning calorimetry and used to determine relaxation times. The results were compared with previously published shear relaxation times and enthalpy recovery data. Results. Very good agreement was observed between dielectric and shear relaxation times, and those obtained from the heating rate dependence of the Tg, for dry indomethacin as a function of temperature above Tg. The introduction of water lowered the dielectric relaxation times of supercooled indomethacin without significantly affecting its fragility. The relaxation times below Tg, found to be lower than those predicted by extrapolation of the data obtained above Tg, were analyzed in the context of the Adam-Gibbs-Vogel equation. Conclusions. The relaxation times of amorphous indomethacin obtained from the heating rate dependence of Tg were in good agreement with those obtained from shear and dielectric measurements, thus validating a relatively simple approach of assessing molecular mobility. The significant molecular mobility of amorphous indomethacin observed below Tg, and the significant plasticizing effects of sorbed water, help to explain why amorphous indomethacin crystallizes well below Tg over relatively short time scales.     

Molecular Mobility of Supercooled Amorphous Indomethacin,Determined by Dynamic Mechanical Analysis

Purpose. To determine the viscosity and the frequency-dependent shear modulus of supercooled indomethacin as a function of temperature near and above its glass transition temperature and from these data to obtain a quantitative measure of its molecular mobility in the amorphous state. Methods. Viscoelastic measurements were carried with a controlled strain rheometer in the frequency domain, at 9 temperatures from 44° to 90°C. Results. The viscosity of supercooled indomethacin shows a strong non-Arrhenius temperature dependence over the temperature range studied, indicative of a fragile amorphous material. Application of the viscosity data to the VTF equation indicates a viscosity of 4.5 × 10¹⁰ Pa.s at the calorimetric Tg of 41°C, and a T₀ of –17°C. From the complex shear modulus and the Cole-Davidson equation the shear relaxation behaviour is found to be non-exponential, and the shear relaxation time at Tg is found to be approximately 100 sec. Conclusions. Supercooled indomethacin near and above its Tg exhibits significant molecular mobility, with relaxation times similar to the timescales covered in the handling and storage of pharmaceutical products.     

Effect of Water Mobility on Drug Hydrolysis Rates in Gelatin Gels

The stability of drugs incorporated in gelatin gels was studied, with a focus on the water mobility in the gels. Trichlormethiazide hydrolysis and kanamycin-catalyzed flomoxef hydrolysis in gelatin gels were chosen as models for apparent first-order and second-order hydrolysis, respectively. The mobility of water in gelatin gels was determined by NMR, ESR, and dielectric relaxation spectroscopies. The amount of bound water in the gels was determined from dielectric relaxation spectra. Spin-lattice relaxation time of water determined by ¹⁷O NMR and rotational correlation time of an ESR probe determined by an ESR probing method were useful in determining the micro viscosity of the gels. The hydrolysis rate of trichlormethi-azide in the gels was found to depend on the amount of free water available for the reaction, while that of flomoxef depended on the micro viscosity of the gels, which reflected the mobility of water molecules. Thus the dependence of hydrolysis rates on the water mobility was influenced by the hydrolysis mechanism.     

Effects of Molecular Interactions on Miscibility and Mobility of Ibuprofen in Amorphous Solid Dispersions With Various Polymers

Hydrogen bonds (HBs) in amorphous solid dispersions may influence physical stability through effects on both drug miscibility and mobility. Amorphous solid dispersions containing the HB-donor ibuprofen (IBP) alone or with one of four model polymers (poly(vinyl pyrrolidone) [PVP], poly(vinyl pyrrolidone/vinyl acetate) [PVP/VA], poly(vinyl acetate) [PVA], or polystyrene [PST]) were monitored by molecular dynamics simulation. HB distributions and contributions of electrostatic, van der Waals, and internal interactions to miscibility and mobility were analyzed versus drug concentration. The probability of IBP-IBP HBs decreases markedly (0.6→0.0) with dilution (100→10% drug) in PVP due to IBP-PVP HBs while dilution in the nonpolar PST has a more modest effect on IBP-IBP HB probability (0.6→0.3). Concentration-dependent Flory-Huggins interaction parameters (χ) were determined to assess drug-polymer miscibility. χ_IBP-PVP values were ?0.9 to ?1.8 with a plateau near 50% w/w PVP, whereas χ_IBP-PST fluctuated near zero (?0.1 to 0.3), suggesting that IBP is more soluble in PVP than in PST. χ_IBP-polymer values in polymers varying in pyrrolidone/acetate composition were in the order PVP (most favorable) > PVP/VA > PVA (least favorable). Decreased local mobility of IBP measured by the atomic fluctuation correlates with more IBP-PVP HBs with increasing PVP content. The opposite trend in IBP-PST may arise from IBP-IBP HB disruption on dilution.     

Time-Dependence of Molecular Mobility during Structural Relaxation and its Impact on Organic Amorphous Solids: An Investigation Based on a Calorimetric Approach

Purpose To develop a calorimetry-based model for estimating the time-dependence of molecular mobility during the isothermal relaxation of amorphous organic compounds below their glass transition temperature (T _g).Methods The time-dependent enthalpy relaxation times of amorphous sorbitol, indomethacin, trehalose and sucrose were estimated based on the nonlinear Adam‐Gibbs equation. Fragility was determined from the scanning rate dependence of T _g. Time evolution of the fictive temperature was determined from T _g, the heat capacity of the amorphous and crystalline forms, and from the enthalpy relaxation data.Results Relaxation time changes significantly upon annealing for all compounds studied. The magnitude of the increase in relaxation time does not depend on any one parameter but on four parameters: T _g, fragility, and the crystal–liquid and glass–liquid heat capacity differences. The obtained mobility data for indomethacin and sucrose, both stored at T _g−16 K, correlated much better with their different crystallization tendencies than did the Kohlrausch‐Williams‐Watts (KWW) equation.Conclusions The observed changes in relaxation time help explain and address the limitations of the KWW approach. Due consideration of the time-dependence of molecular mobility upon storage is a key element for improving the understanding necessary for stabilizing amorphous formulations.     

药物离子淌度，分子量和离子导入的关系

应用离子淌度-孔模型研究了药物物化性质与离子导入的关系。以盐酸丁卡因、盐酸普鲁卡因、盐酸达克罗宁、盐酸利多卡因和盐酸布比卡因等5种局麻药为模型药物,分别测定它们的离子淌度(u),并采用双室扩散池法,测定它们通过离体大鼠腹部皮肤时的离子导入增渗倍数(ER)。并以logER对分子量(MW)和loguj线性回归得logER=1.961-5.85×10     

Distribution and Effect of Water Content on Molecular Mobility in Poly(vinylpyrrolidone) Glasses: A Molecular Dynamics Simulation

Purpose This work explores the distribution of water and its effects on molecular mobilities in poly(vinylpyrrolidone) (PVP) glasses using molecular dynamics (MD) simulation technology.Methods PVP glasses containing 0.5% and 10% w/w water and a small amount of ammonia and Phe-Asn-Gly were generated. Physical aging processes and associated structural and dynamic properties were monitored vs. time for periods up to 0.1 μs by MD simulation.Results Increasing water content from 0.5% to 10% w/w was found to reduce the T_g by about 90 K and increase the rates of volume and enthalpy relaxation. At 0.5% w/w, water molecules are mostly isolated and uniformly distributed while at 10% w/w, water distribution is markedly heterogeneous, with strands of water molecules occupying channels between the polymer chains. At 10% w/w, each water molecule has an average of 2.0 neighboring water molecules. The plasticization effects of water were revealed in diffusion coefficient increases of 3.7-, 7.3-, and 7.6-fold for water, ammonia, and the individual polyvinylpyrrolidone segments, respectively, and in shorter relaxation times (37- to 47-fold) for rotation of polymer segments with an elevation in water content from 0.5% to 10% w/w. Water diffusivity was found to linearly correlate with the number of neighboring water molecules. Rotation of the PVP segments is comprised of a fast wobble motion within a highly restrained cavity and a slow rotation over a wider angular space. Only the slow rotation was shown to be significantly affected by water content.Conclusions Water distribution in the PVP glass is highly heterogeneous at 10% w/w water, reflecting the formation of water strands or small clusters rather than complete phase separation. Local enhancement of mobility with increasing water content has been demonstrated using MD simulations.     

丹参酮IIA/速释辅料二元固态溶液的玻璃化转变温度研究

目的 探索丹参酮IIA与不同速释辅料的相容性及对辅料玻璃化转变温度的影响。方法 采用溶剂法制备不同种类及比例的丹参酮IIA/速释辅料二元固态溶液,并进行差示扫描量热分析,测定其玻璃化转变温度。结果 丹参酮IIA与3种速释辅料均具有良好的相容性,不同种类辅料及比例的二元固态溶液,受到药物与辅料间的分子作用力、辅料的抗增塑作用等的影响,可对体系的玻璃化转变温度产生不同程度的改变。结论 本研究为以聚合物HPMC K4M、Kollidon VA64或Soluplus为辅料制备具有速释特性的丹参酮IIA无定型态给药体系提供了技术支持。     

Comparison of Molecular Mobility in the Glassy State Between Amorphous Indomethacin and Salicin Based on Spin-Lattice Relaxation Times

Purpose. The purpose of the current study was to evaluate the molecular mobility of amorphous indomethacin and salicin in the relaxed glassy state based on spin-lattice relaxation times (T_1c) and to clarify the effects of molecular mobility on their physical stability.Methods. Pulverized glassy amorphous indomethacin and salicin samples were completely relaxed, and the T_1c values were investigated using solid-state ¹³C-nuclear magnetic resonance (NMR) at temperatures below the glass transition temperature (T_g). All NMR spectra were obtained using the T_1c measurement method combined with variable-amplitude cross-polarization, the Torchia method, and total sideband suppression method.Results. The T_1c value of amorphous indomethacin indicated that 73% of carbons were in a state of monodispersive relaxation, suggesting that the amorphous state was relatively homogeneous and restricted, particularly in backbone carbons. On the other hand, 92% of carbons of amorphous salicin exhibited both fast and slow biphasic relaxation. Individual structures of the salicin molecules behaved heterogeneously, and thus the entire molecule showed relatively fast local as well as slow mobility.Conclusions. At temperatures below T_g, amorphous salicin had relatively greater molecular mobility than amorphous indomethacin. This difference in the molecular mobility of the two compounds is correlated with their crystallization behavior. Solid-state ¹³C NMR provides valuable information on the physical stability of amorphous pharmaceuticals.     

The Influence of Polymer Glass Transition Temperature and Molecular Weight on Drug Release from Tablets Containing Poly(DL-lactic Acid)

Five molecular weight grades of poly(DL-lactic acid) were characterized using gel permeation chro-matography, differential scanning calorimetry, and viscometry to determine the effect of molecular weight on the glass transition temperature and the intrinsic viscosity. In addition, dynamic mechanical thermal analysis was used to assess the dynamic storage modulus and the damping factor of the polymer samples by detecting motional and structural transitions over a wide temperature range. Significant relationships were found between the molecular weight and these polymer properties. The five grades of poly(DL-lactic acid) were also incorporated as binders into matrix tablet formulations containing the model drug theophylline and microcrystalline cellulose. Dissolution studies showed significant correlations between the properties of the polymer and the matrix release profiles of the tablets. The release of theophylline slowed down progressively as the polymer molecular weight increased. The differences in release became less significant and reached a limiting asymptotic value as the molecular weight increased to 138,000. Further, tablet index testing was utilized to determine the compaction properties of the polymer granulations. Although there was no correlation with the molecular weight of PL A, brittle fracture index testing indicated very low brittleness for all granulations tested. However, bonding index determinations correlated very well with both the physical-mechanical properties of the polymer and drug release profiles.     

Rapid Assessment of the Structural Relaxation Behavior of Amorphous Pharmaceutical Solids: Effect of Residual Water on Molecular Mobility

Purpose Use RH-perfusion microcalorimetry and other analytical techniques to measure the interactions between water vapor and amorphous pharmaceutical solids; use these measurements and a mathematical model to provide a mechanistic understanding of observed calorimetric events.Materials Isothermal microcalorimetry was used to characterize interactions of water vapor with a model amorphous system, spray-dried raffinose. Differential scanning calorimetry was used to measure glass transition temperature, T _g. High-sensitivity differential scanning calorimetry was used to measure enthalpy relaxation. X-ray powder diffraction (XRPD) was used to confirm that the spray-dried samples were amorphous. Scanning electron microscopy (SEM) was used to examine particle morphology. Gravimetric vapor sorption was used to measure moisture sorption isotherms. Thermogravimetric analysis (TGA) was used to measure loss on drying.Results A moisture-induced thermal activity trace (MITAT) provides a rapid measure of the dependence of molecular mobility on moisture content at a given storage temperature. At some relative humidity threshold, RH_m, the MITAT exhibits a dramatic increase in the calorimetric rate of heat flux. Simulations using calorimetric data indicate that this thermal event is a consequence of enthalpy relaxation.Conclusions RH-perfusion microcalorimetry is a useful tool to determine the onset of moisture-induced physical instability of glassy pharmaceuticals and could find a broad application to determine appropriate storage conditions to ensure long-term physical stability. Remarkably, thermal events measured on practical laboratory timescales (hours to days) are relevant to the stability of amorphous materials on much longer, pharmaceutically relevant timescales (years). The mechanistic understanding of these observations in terms of enthalpy relaxation has added further value to the use of RH-perfusion calorimetry as a rapid means to characterize the molecular mobility of amorphous solids.