Electrolyte-Induced Changes in Glass Transition Temperatures of Freeze-Concentrated Solutes

Addition of electrolytes to solutions of non-crystallizing solutes can cause a significant decrease in the glass transition temperature (T_g) of the maximally freeze-concentrated solution. For example, addition of 2% sodium chloride to 10% solutions of dextran, PVP, lactose, and sucrose causes a decrease in T_g of 14° to 18°C. Sodium phosphate has a smaller effect on T_g, and is unusual in that 1% to 2% sodium phosphate in 10% PVP causes a second glass transition to be observed in the low-temperature thermogram, indicating a phase separation in the freeze concentrate. Comparison of DSC thermograms of fast-frozen solutions of sucrose with and without added sodium chloride shows that electrolyte-induced reduction of T_gis not caused by a direct plasticizing effect of the electrolyte on the freeze concentrate. Measurement of unfrozen water content as a function of temperature by a pulsed nmr method shows that the most likely mechanism for electrolyte-induced changes in T_g is by increasing the quantity of unfrozen water in the freeze concentrate, where the unfrozen water acts as a plasticizer and decreases T_g. The correlation time (_c) of water in the freeze concentrate is in the range of 10^–7 to 10^–8 seconds. The results underscore the importance of minimizing the amount of added salts to formulations in-tended for freeze drying.     

Determination of the Glass Transition Temperatures of Some New Methyl Methacrylate Copolymers Using Modulated Temperature Differential Scanning Calorimetry (MTDSC)

Purpose. The purpose of this study was to determine the glass transition temperatures of new graft copolymers using Modulated Temperature Differential Scanning Calorimetry (MTDSC), and to assess the differences between starch and cellulosic derivatives of methyl methacrylate and between two different drying methods used in their preparation. Methods. Graft copolymers of methyl methacrylate were synthesized and dried by oven or freeze-drying. Surface area measurements and different thermal analysis techniques (Differential Scanning Calorimetry (DSC), Thermogravimetric analysis (TGA) and MTDSC) were used to characterize these copolymers. Results. DSC was not sensitive enough to identify the T_gs of the copolymers, however they were clearly identifiable by MTDSC. T_g values obtained may depend on the method of preparation that also altered their physical characteristics e.g. specific surface area. Cellulose derivatives showed lower T_gs than starch derivatives. The results also depended on the drying method used, thus, freeze dried products had slightly lower T_gs than oven dried products. Conclusions. MTDSC represents a useful thermal technique that allows the identification of glass transitions in these new copolymers with higher sensitivity and resolution than conventional DSC, separating the transition from overlapping phenomena such as decomposition or dehydration. The T_g of this new class of copolymers appeared to be dependent on polymer composition and drying method used.     

Evaluation of the Physical Stability of Freeze-Dried Sucrose-Containing Formulations by Differential Scanning Calorimetry

Freeze-dried samples of sucrose with buffer salts, amino acids, or dextran have been analyzed with differential scanning calorimetry (DSC) to evaluate the use of DSC thermograms in predicting the physical storage stability. The glass transition temperature, T _g, of the amorphous cake, crystallization, and melting of sucrose are observed with DSC. T _g appeared to be an important characteristic of the physical stability of the amorphous freeze-dried cake. A storage temperature above T _g results in collapse or shrinkage of the cake, which for a sucrose-based formulation, may be accompanied by crystallization of the sucrose. The T _g of the amorphous sucrose is influenced by other components present in the cake. Dextran-40 raised T _g, while the addition of glycine to the formulation lowered T _g. The residual moisture content strongly influences T _g, since water acts as a plasticizer of the system; the higher the moisture content, the lower the T _g and the less physically stable the freeze-dried cake. Crystallization of amorphous sucrose is shown to be inhibited by high molecular weight components or ionic compounds. DSC analysis of freeze-dried cakes proved to be a powerful tool in formulation studies.     

差示扫描量热法在药品检验中的研究进展

差示扫描量热分析（DSC）具有简便快速、重现性好、且避免繁杂的样品制备过程等优点。本文着重综述了近年来DSC在包括纯度测定、晶型表征、熔点检测、热稳定性检查和中药定性定量分析等药品质量控制研究中的多方面应用进展情况,并展望了其未来发展前景。     

Effect of Cations and Anions on Glass Transition Temperatures in Excipient Solutions

The purpose of this study was to investigate the effects of cations and anions of various electrolytes on the glass transition temperature (Tg') of frozen solutions of excipients commonly used in freeze-drying. The effect of electrolyte concentration on freezable water content was also investigated by measuring the enthalpy of melting (ΔH) using Differential Scanning Calorimetry (DSC). Cations and anions induce changes in Tg' of frozen solutions of commonly used parenteral excipients. These changes are dependent on the properties of the excipients used. Tg' values of 5% w/v solutions of maltose, trehalose, sucrose, dextran 40, and polyvinylpyrrolidone (PVP, 17K) were determined as a function of sodium chloride (NaCl) or potassium chloride (KCl) concentrations. In general, a significant decrease in Tg' was observed as a function of increasing the electrolyte concentration. For the disaccharide solutions, the decrease in Tg' due to the addition of NaCl or KCl was similar in magnitude, indicating that changing the cation from K⁺ to Na⁺ had no effect on Tg'. However, the decrease in Tg' for the PVP solution due to the addition of KCl was greater than that observed by the addition of NaCl. The differences in the electrolyte-induced changes on Tg' between the disaccharides and PVP may be potentially attributed to the formation of complexes between the cations and the properly oriented hydroxyl groups in the sugars leaving the anions (Cl^? ions) to exert their effect on Tg'. While zero cation effect would be consistent with these results for the disaccharides, these results do not mean that the cation effects are zero; they only mean that the cation effects are the same. For the PVP solution, K⁺ and Na⁺ ions are not engaged in complex formation with PVP due to the lack of hydroxyl groups. We hypothesize that the structure-breaking K⁺ ions increase the fluidity of water and exert a greater plasticizing effect on Tg', leading to a more significant decrease in Tg' than the structure-making Na⁺ ions, which increase the viscosity of water. The decrease in Tg' of frozen solutions of pharmaceutical excipients caused by the addition of electrolytes may be primarily attributed to an increase in the unfrozen plasticizing water surrounding the excipient molecules. Formulation scientists should evaluate the use of electrolytes in the formulation development of lyophilized products containing commonly used excipients. Electrolytes are often needed as stabilizers for protein formulations; however, their selection and use should be properly evaluated. Because electrolytes cause a decrease in Tg' as a function of electrolyte concentration, it is recommended that the minimum electrolyte concentration needed to maintain product stability should be used to minimize the effect of the electrolyte on lowering the Tg'.     

差示扫描量热法评价聚山梨酯80质量

目的研究差示扫描量热法（differential scanning calorimetry,DSC）作为聚山梨酯80质量评价方法的可行性。方法采用DSC对8个不同品牌的聚山梨酯80进行表征,分析DSC图谱中熔点和峰型;采用酶标法测定聚山梨酯80对家兔体外溶血的影响;采用肌酸激酶（creatine kinase,CK）试剂盒测定聚山梨酯80对L6细胞的刺激性。结果同一品牌同一批聚山梨酯80熔点相对标准偏差（relative standard deviation,RSD）在5%以内,重复性良好。DSC热分析图具有较好的灵敏度,可甄别批次间成分存在的一定差异。DSC热分析图的差异和品质有直接的相关性,不同品牌的聚山梨酯80呈现差异较大的热分析图,表明这些样品成分差异较大,这一结果得到了体外溶血性和骨骼肌刺激性实验结果的证实。结论DSC技术可以作为聚山梨酯80质量评价的一种半定量方法。     

Estimation of Drug Solubility in Polymers via Differential Scanning Calorimetry and Utilization of the Fox Equation

The solubility of drugs in polyethylene glycol 400 (PEG 400) was estimated and rank ordered using a differential scanning calorimetry (DSC) method and the Fox Equation. Drug-polymer binary mixtures of six compounds (Ibuprofen, Indomethacin, Naproxen, and three proprietary compounds: PC‐1 through PC-3) with PEG 400 were heat treated using a three-cycle DSC method to establish a correlation between equilibrium solubility and temperature. Thermal events such as heat of fusion, heat of recrystallization and glass transition temperature, T_g, were used to calculate the drug solubility at multiple higher temperatures through the Fox Equation. Subsequently, a van't Hoff plot was constructed to estimate the drug solubility at room temperature, and the values were compared with those measured by HPLC. With the exception of Naproxen, room temperature solubilities of the remaining drug compounds in PEG 400 were determined by this thermal method approach, and compared with those measured by HPLC: 26.7% vs. 24.7% for Ibuprofen, 5.8% vs. 9.6% for Indomethacin, 3.1 % vs. 1.5% for PC-1, 2.3% vs. 1.3% for PC-2, and 1.4% vs. 0.2% for PC-3 in PEG 400. There was good concordance in solubility rank order estimates between the two methods. These collective results support the potential utility of the thermal method as an alternative to other methods for estimation of drug solubility in polymers which is an important determinant in the design of physically-stable amorphous systems.     

Measurement of Glass Transition Temperatures in Freeze Concentrated Solutions of Non-Electrolytes by Electrical Thermal Analysis

The electrical resistance (R) of frozen aqueous solutions was measured as a function of temperature in order to determine whether this technique can be applied for determination of glass transition temperatures of maximally freeze concentrated solutions (T_g) of non-electrolytes which do not crystallize during freezing. Electrical thermal analysis (ETA) thermograms of frozen solutions containing the solute alone show a gradual change in slope over the temperature range of interest, with no inflection point which corresponds to T_g. However, addition of low levels (about 0.1%) of electrolyte changes the shape of the thermogram into a biexponential function where the intersection of the two linear portions of the log (R) vs. T plot corresponds to the glass transition region. The total change in log (R) over the temperature range studied increases as the ionic radius of the reporter ion increases. The sharpest inflection points in the log (R) vs T curves, and the best correlation with DSC results, were obtained with ammonium salts. T_g values measured by ETA were compared with values measured by DSC. DSC thermograms of solutes with and without electrolyte (0.1%) show that the electrolyte decreases T_g by about 0.5 to 1.0°C. However, T_g values measured by ETA are somewhat higher than those measured by DSC, and difference between the two methods seems to increase as T_g decreases. T_g as measured by ETA is less heating rate dependent than DSC analysis, and ETA is a more sensitive method than DSC at low solute concentrations and at low heating rates. Results of electrical thermal analysis of frozen solutions are compared and contrasted with the electrical resistance vs. temperature behavior of polymer-electrolytes. ETA appears to be a useful complementary technique to DSC for characterizing formulations intended for freeze drying.     

The Reversibility of Absorption Promoter Interaction with Red Blood Cell Membranes Studied with Differential Scanning Calorimetry

Absorption promoters, or adjuvants, are used to enhance the gastrointestinal absorption of poorly absorbed drugs such as macromolecules. In the present work, adjuvant–membrane interactions have been studied by differential scanning calorimetry (DSC) using red blood cell (RBC) membranes as model membrane. These interactions caused temperature shifts, amplitude changes, and broadening of the RBC transitions. Because more than one transition may be simultaneously affected by a given adjuvant, complex overlappings occur. Gaussian modeling and nonlinear regression analysis, therefore, were used to resolve these transitions. A correlation, which may serve as an indicator of adjuvant potency, was found between adjuvant concentration and induced transition temperature shifts. Further, these shifts recovered to baseline after successive washings with buffer (for most adjuvants). Sodium lauryl sulfate induced transition alterations, however, never recovered. Thus the DSC might be useful in monitoring reversible adjuvant–membrane interactions.     

差示扫描量热法测定比沙可啶原料药纯度及不确定度评定

目的:建立测定比沙可啶原料药纯度及不确定度评定的方法。方法:采用差示扫描量热(DSC)法对比沙可啶原料药纯度进行测定,确定最优检测条件;依据相关标准,对仪器校准铟标定焓变、测量重复性、称量过程、仪器温度偏差、系统软件偏差5个不确定度分量进行系统分析。采用高效液相色谱(HPLC)法对结果进行验证。结果:置信概率P为0.95时,采用DSC法测定比沙可啶原料药纯度结果的标准值及其不确定度为(99.88±0.06)%。其中称量过程、仪器温度偏差和系统软件偏差对总不确定度影响较大。DSC法与HPLC法测定结果一致。结论:所建立的DSC法可以快速、准确地测定比沙可啶原料药纯度,为其纯度测定提供了一种新的分析方法。DSC仪器的定期校准检定和称量过程的严格控制有利于提高DSC法测定的准确度。     

差示扫描量热法测定磺胺类化学对照品的纯度

目的 采用差示扫描量热法(differential scanning calorimetry,DSC)测定磺胺类化学对照品纯度。方法 采用优化DSC实验参数,载气流速50 mL·min^-1,升温速率3 ℃·min^-1,称样量1.3~2.0 mg,对7种磺胺类化学对照品进行纯度分析。结果 DSC测得磺胺噻唑纯度为99.9%,磺胺甲二唑为99.9%,磺胺甲氧嗪为99.8%,磺胺嘧啶为99.8%,磺胺甲噁唑为99.9%,磺胺多辛为99.5%和磺胺二甲嘧啶为99.9%,其结果与质量平衡法测定结果基本一致。结论 DSC简便、快捷、无需标准物质,为磺胺类化学对照品纯度测定提供了新的检测方法。     

High Sensitivity Differential Scanning Calorimetry Study of DNA-Cationic Liposome Complexes

PURPOSE: To investigate plasmid DNA interactions with liposomes prepared from dimyristoylglyceroethylphosphocholine (EDMPC) and DOPE using high sensitivity differential scanning calorimetry (HSDSC). MATERIALS AND METHODS: Large unilamellar liposomes of EDMPC with DOPE (mol ratio 0-50%) were prepared. Plasmid DNA was added to give a final DNA/lipid (-/+) charge ratio of 0.5. Samples were placed into an HSDSC and cooled to 3 degrees C, held isothermally for 30 min and then the temperature was ramped to 120 degrees C at a rate of 1 degree C/min. RESULTS: On heating EDMPC liposomes, the main phase transition occurred at 21.2 degrees C, with a low temperature shoulder on the endothermic peak. At low DOPE concentrations the main phase transition temperatures and enthalpies of transition were lower than for pure EDMPC, with a peak corresponding to a pure EDMPC phase occurring at DOPE concentrations of 12-17 mol%. At 50 mol%, no main transition endotherm was observed. DNA solution produced two endothermic peaks with numerous 'satellite' peaks indicating thermal denaturation. DNA binding to EDMPC changed the shape of the thermogram, indicating alteration in lipid packing within the bilayer. DNA induced demixing in the bilayers of DOPE-containing liposomes. CONCLUSION: HSDSC provided information for characterizing liposome formulations and DNA interactions with such vesicles.     

Polymorphic Behavior of Sprayed Lipid Micropellets and Its Evaluation by Differential Scanning Calorimetry and Scanning Electron Microscopy

Considering the importance of polymorphism occurring in solid dosage forms causing instability, the polymorphic behavior of spray-dried and -congealed lipid micropellets was examined by differential scanning calorimetry and scanning electron microscopy. The results showed that both of the spraying processes exert an important effect on their polymorphic and crystallization properties. In spray-drying, due to the rapid solvent evaporation, the obtained lipid micropellets possess an unstable polymorphic form. This unstable form transforms gradually toward a stable form by storage at elevated temperatures. The same modifications were observed with spray-congealed lipid micropellets. The type of glyceride (composition, chain length), solvent and drugs (estradiol cypionate, medroxyprogesterone acetate) and, further, the presence of a stabilizing agent such as lecithin affect the polymorphic transition and its rate.     

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.     

Determination of the Solubility of Crystalline Low Molar Mass Compounds in Polymers by Differential Scanning Calorimetry

A mathematical equation has been derived to calculate the liquidus for a binary system consisting of an amorphous polymer and a crystalline low molar mass compound. The experimental input to this equation is an interaction enthalpy, which is derived from the variation of the melting enthalpy with composition in differential scanning calorimetry (DSC) experiments. The predictive power of the equation has been tested with mixtures of acetylsalicylic acid, carbamazepine, or intraconazole with poly(ethylene glycol) as well as mixtures of carbamazepine with poly(acrylic acid), poly(hydroxystyrene), or poly(vinylpyrrolidone). It has been confirmed that the evaluation of the melting enthalpy in DSC is a suitable method to identify the preferred solute-polymer combinations for thermodynamically stable molecular dispersions. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:1673-1679, 2014     

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.     

Implications of Global and Local Mobility in Amorphous Sucrose and Trehalose as Determined by Differential Scanning Calorimetry

Purpose  To investigate the local and global mobility in amorphous sucrose and trehalose and their potential implications on physical stability. Methods  Amorphous sucrose was prepared by lyophilization while amorphous trehalose was prepared by dehydration of trehalose dihydrate. The variation in the effective activation energy of α-relaxation through glass transition has been determined by applying an isoconversional method. β-Relaxations were detected as shallow peaks, at temperatures below the glass transition temperature, caused by annealing glassy samples at different temperatures and subsequently heating at different rates in a differential scanning calorimeter. The effect of heating rate on the β-relaxation peak temperature formed the basis for the calculation of the activation energy. Results  α-Relaxations in glassy trehalose were characterized by larger activation energy barrier compared to sucrose, attributable to a more compact molecular structure of trehalose. The effect of temperature on viscous flow was greater in trehalose which can have implications on lyophile collapse. The size of the cooperatively rearranging regions was about the same for sucrose and trehalose suggesting similar dynamic heterogeneity at their respective glass transition temperatures. The activation energy of β-relaxations increased with annealing temperature due to increasing cooperative motions and the increase was larger in sucrose. The temperature at which β-relaxation was detected for a given annealing time was much less in sucrose implying that progression of local motions to cooperative motions occurred at lower temperatures in sucrose. Conclusions  Trehalose, having a lower free volume in the glassy state due to a more tightly packed molecular structure, is characterized by larger activation energies of α-relaxation and experiences a greater effect of temperature on the reduction in the activation energy barrier for viscous flow. The pronounced increase in cooperative motions in sucrose upon annealing at temperatures below (T _g −50) suggest that even a small excursion in temperature could result in a significant increase in mobility.     

Assessment of Polymer-Polymer Interactions in Blends of HPMC and Film Forming Polymers by Modulated Temperature Differential Scanning Calorimetry

Purpose. To assess the miscibility and phase behavior of binary blendsof hydroxypropylmethyl cellulose (HPMC) with hydroxypropylcellulose (HPC), methylcellulose (MC), and polyvinylpyrrolidone (PVP). Methods. Polymer-polymer miscibility was assessed by measurementof the glass transition temperature (Tg) and the width of the glasstransition temperature (W-Tg), using modulated temperaturedifferential scanning calorimetry (MTDSC). Results. HPMC K4M/PVP and HPMC E5/MC blends were miscibleas evidenced by a single, composition dependent, Tg throughout theentire composition range. HPMC/HPC blends were immiscible at allcompositions. For the miscible blends, the variation in Tg with blendcomposition was compared to the values predicted by the Fox andCouchman-Karasz equations. At intermediate blend compositions,HPMC K4M/PVP blends exhibited negative deviations from idealbehavior. The Tg of the HPMC E5/MC blends was found to followthe Fox equation. The W-Tg measurements of the miscible blends gaveevidence of phase separation at certain compositions. Conclusions. MTDSC was shown to be a useful technique incharacterizing the interactions between some commonly used pharmaceuticalpolymers.     

Effect of pH, Counter Ion, and Phosphate Concentration on the Glass Transition Temperature of Freeze-Dried Sugar-Phosphate Mixtures

PURPOSE: The aim of the present work is to study the interaction of phosphate salts with trehalose and sucrose in freeze-dried matrices, particularly the effect of the salts on the glass transition temperature (Tg) of the sugars. METHODS: Freeze-dried trehalose and sucrose systems containing different amounts of sodium or potassium phosphate were analyzed by differential scanning calorimetry to determine the Tg and by Fourier-transform infrared spectroscopy (FTIR) analysis to evaluate the strength of the interaction between sugars and phosphate ions. RESULTS: Sucrose-phosphate mixtures show an increase in Tg up to 40 degrees C in a broad pH range (4-9) compared to that of pure sucrose. Sucrose-phosphate mixtures exhibit a higher Tg than pure sucrose while retaining higher water contents. Trehalose-phosphate mixtures (having a Tg of 135 degrees C at a pH of 8.8) are a better option than pure trehalose for preservation of labile materials. The -OH stretching of the sugars in the presence of phosphates decreases with increase in pH, indicating an increase in the sugar-phosphate interaction. CONCLUSIONS: Sugar-phosphate mixtures exhibit several interesting features that make them useful for lyophilization of labile molecules; Tg values much higher than those observed for the pure sugars can be obtained upon the addition of phosphate.     

Effect of Compaction Temperature on Consolidation of Amorphous Copolymers with Different Glass Transition Temperatures

Purpose. The purpose of this study was to relate the combination of glass transition temperature (T _g) and temperature of measurement with the mechanical and compaction properties of some test materials. Methods. Copolymers with different T _gs were synthesised by free radical copolymerisation of methyl methacrylate with lauryl methacrylate. Elastic moduli were measured by dynamic mechanical analysis at different strain rates and temperatures. Compaction experiments were performed at different compaction speeds and temperatures. Results. The difference between temperature of measurement and T _g appears to determine both elastic modulus and yield strength completely. They both decrease with decreasing difference between temperature of measurement and Tg and increase with strain rate. At temperatures of measurement higher than the T _g, the elastic modulus is extremely low because the materials behave as rubbers. Consequently, the amount of energy stored during compaction decreases when the compaction temperature approaches the T _g and increases with strain rate. When the compaction temperature is higher than the T _g, the amount of stored energy is extremely large. The compaction experiments show that the final tablet porosity is completely determined by stress relaxation phenomena. Consequently, the final tablet porosity follows exactly the same relation as that of stored energy. Conclusions. The final tablet porosity is unequivocally determined by the amount of stored energy. This implies that tablet production at a temperature of about 20 K under the glass transition temperature of the material yields tablets with minimum porosity.