In Situ Dehydration of Carbamazepine Dihydrate: A Novel Technique to Prepare Amorphous Anhydrous Carbamazepine

The purposes of this project were to prepare amorphous carbamazepine by dehydration of crystalline carbamazepine dihydrate, and to study the kinetics of crystallization of the prepared amorphous phase. Amorphous carbamazepine was formed and characterized in situ in the sample chamber of a differential scanning calorimeter (DSC), a thermogravimetric analyzer (TGA), and a variable temperature x-ray powder diffractometer (VTXRD). It has a glass transition temperature of 56°C and it is a relatively strong glass with a strength parameter of 37. The kinetics of its crystallization were followed by isothermal XRD, under a controlled water vapor pressure of 23 Torr. The crystallization kinetics are best described by the three-dimensional nuclear growth model with rate constants of 0.014, 0.021, and 0.032 min¹ at 45, 50, and 55°C, respectively. When the Arrhenius equation was used, the activation energy of crystallization was calculated to be 74 kJ/mol in the presence of water vapor (23 Torr). On the basis of the Kissinger plot, the activation energy of crystallization in the absence of water vapor (0 Torr water vapor pressure) was determined to be 157 kJ/mol. Dehydration of the dihydrate is a novel method to prepare amorphous carbamazepine; in comparison with other methods, it is a relatively gentle and effective technique.     

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.     

Using Milling to Explore Physical States: The Amorphous and Polymorphic Forms of Sulindac

This article shows how milling can be used to explore the phase diagram of pharmaceuticals. This process has been applied to sulindac. A short milling has been found to trigger a polymorphic transformation between form II and form I upon heating which is not seen in the nonmilled material. This possibility was clearly demonstrated to result from crystalline microstrains induced by the mechanical shocks. A long milling has been found to induce a total amorphization of the material. Moreover, the amorphous fraction produced during milling appears to have a complex recrystallization upon heating which depends on the milling time. The investigations have been mainly performed by differential scanning calorimetry and powder X-ray diffraction.     

Influence of Environmental Conditions on the Kinetics and Mechanism of Dehydration of Carbamazepine Dihydrate

ABSTRACT

The object of this project was to study the influence of temperature and water vapor pressure on the kinetics and mechanism of dehydration of carbamazepine dihydrate and to establish the relationship between the dehydration mechanism and the solid-state of the anhydrous phase formed, Three experimental techniques were utilized to study the kinetics of dehydration of carbamazepine dihydrate (C₁₅H₁₂N₂O·2H₂O)-thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and variable temperature powder X-ray diffractometry (VYXRD). These techniques respectively provide information about the changes in weight, heat flow and solid-state (phase) during the dehydration process. The instrumental setup was modified so that simultaneous control of both the temperature and the water vapor pressure was possible. The experiments were carried out at different temperatures, ranging from 26 to 64°C. In the absence of water vapor, the dehydration followed the 2-dimen-sional phase boundary controlled model at all the temperatures studied. In the next stage, the water vapor pressure was altered while the studies were carried out at a single temperature of 44°C. The dehydration was 2-dimensional phase boundary controlled at water vapor pressures ≤5.1 torr while the Avrami-Erofeev kinetics (3-dimensional nucleation) was followed at water vapor pressures ≥ 12.0 torr. In the former case, the anhydrous phase formed was X-ray amorphous while it was the crystalline anhydrous γ-carbamazepine in the latter. Thus a relationship between the mechanism of dehydration and the solid-state of the product phase was evident. The dehydration conditions influence not only the mechanism but also the solid-state of the anhydrous phase formed. While the techniques of TGA and DSC have found extensive use in studying dehydration reactions, VTXRD proved to be an excellent complement in characterizing the solid-states of the reactant and product phases.     

用差示扫描量热法测定头孢菌素类药物的热降解稳定性

本文用差示扫描量热法(DSC)试验了十二个常用的有代表性的头孢菌素的热降解稳定性,用Kissinger和Ozawa方程求各头孢菌素的热降解动力学参数(主要为活化能)。在所有头孢菌素的DSC曲线中均未见有熔点峰,故不能用量热法测定其纯度,但它们的放热峰均甚陡直、明锐,而且峰温的重现性良好,可供鉴别这些头孢菌素用。     

Prediction of the Long-Term Dissolution Performance of an Immediate-Release Tablet Using Accelerated Stability Studies

A slowdown in dissolution performance has been observed for an immediate release tablet formulation during long-term stability testing. The slowdown was successfully predicted using an accelerated stability study in which the dissolution was tested over a range of temperatures, humidity conditions and storage times. The slowdown was quantified using a calculated parameter referred to as the “acceleration factor” (AF); this is the degree by which the timescale (x-axis) of a dissolution profile needs to be scaled to overlay it on to the dissolution profile obtained at the initial timepoint. The “AF” approach was applicable because it was observed that the shape of the dissolution profile remains consistent even though different dissolution rates were obtained. Under the accelerated stability conditions, the AF is observed to follow an “exponential decay” curve. A predictive model for the long-term stability dissolution was obtained by modeling both the plateau level and the rate constant for the exponential decay curve as functions of temperature and humidity. The long-term stability of product A in packaging was successfully predicted using this model in combination with simulations of the changing relative humidity conditions inside the packaging.     

Determination of the Structural Relaxation Enthalpy Using a Mathematical Approach

Structural relaxation is a well-known phenomenon in amorphous materials such as amorphous solid dispersions. It is generally understood as a measure for molecular mobility and has been shown to impact certain material properties such as the dissolution rate. Several quantification methods to evaluate structural relaxation using differential scanning calorimetry have been proposed in the past, but all approaches exhibit disadvantages. In this work, a mathematical model was developed and fitted to calorimetric data enabling the analysis of the structural relaxation enthalpy by separating the structural relaxation peak from the underlying glass transition. The proposed method was validated using a parameter sensitivity analysis. Differently stressed amorphous samples were analyzed applying the new model and the results were compared to commonly applied quantification methods in literature. The proposed method showed high robustness and accuracy and overcame the observed disadvantages of the established methods. The heating rate dependence of the calculated structural relaxation enthalpy was in accordance with theoretical considerations of previous studies, supporting the validity of the results. Thus, the proposed model is suitable to accurately quantify the degree of structural relaxation and should be a valuable tool for further investigations regarding the impact of structural relaxation on material properties.     

Correlationship of Drug-Polymer Miscibility,Molecular Relaxation and Phase Behavior of Dipyridamole Amorphous Solid Dispersions

In present work, a correlationship among quantitative drug-polymer miscibility, molecular relaxation and phase behavior of the dipyridamole (DPD) amorphous solid dispersions (ASDs), prepared with co-povidone (CP), hydroxypropyl methylcellulose phthalate (HPMC P) and hydroxypropyl methylcellulose acetate succinate (HPMC AS) has been investigated. Miscibility predicted using melting point depression approach for DPD with CP, HPMC P and HPMC AS at 25 °C was 0.93% w/w, 0.55% w/w and 0.40% w/w, respectively. Stretched relaxation time (τ^β) for DPD ASDs, measured using modulated differential scanning calorimetry (MDSC) at common degree of undercooling, was in the order of DPD- CP > DPD-HPMC P > DPD-HPMC AS ASDs. Phase behavior of 12 months aged (25 ± 5 °C and 0% RH) spray dried 60% w/w ASDs was tracked using MDSC. Initial ASD samples had homogeneous phase revealed by single glass transition temperature (T_g) in the MDSC. MDSC study of aged ASDs revealed single-phase DPD-CP ASD, amorphous-amorphous and amorphous-crystalline phase separated DPD-HPMC P and DPD-HPMC AS ASDs, respectively. The results were supported by X-ray micro computed tomography and confocal laser scanning microscopy studies. This study demonstrated a profound influence of drug-polymer miscibility on molecular mobility and phase behavior of ASDs. This knowledge can help in designing “physical stable” ASDs.     

头孢呋辛钠的热稳定性及其热分解动力学研究

目的:研究头孢呋辛钠的热稳定性。方法:采用热重分析法和差式扫描量热法测定头孢呋辛钠在氮气和空气中的热分解曲线,借助经典的非等温速率方程Kissinger和Ozawa-Flynn-Wall方法计算该药物的热分解动力学参数。结果:2种方法计算头孢呋辛钠在空气中的热分解动力学参数分别为:表观活化能139.2、139.3kJ.mol-1,指前因子(ln值)18.64、18.66s-1;在氮气中上述参数分别为106.8、108.5kJ.mol-1,14.64、14.85s-1。2种计算方法结果无显著性差异。结论:头孢呋辛钠具有很高的活化能,热稳定性好,在氮气中更稳定。     

Effect of Moisture on the Stability of a Lyophilized Humanized Monoclonal Antibody Formulation

Purpose. To determine the effect of moisture and the role of the glass transition temperature (T_g) on the stability of a high concentration, lyophilized, monoclonal antibody. Methods. A humanized monoclonal antibody was lyophilized in a sucrose/histidine/polysorbate 20 formulation. Residual moistures were from 1 to 8%. T_g values were measured by modulated DSC. Vials were stored at temperatures from 5 to 50°C for 6 or 12 months. Aggregation was monitored by size exclusion chromatography and Asp isomerization by hydrophobic interaction chromatography. Changes in secondary structure were monitored by Fourier transform infrared (FTIR). Results. T_g values varied from 80°C at 1% moisture to 25°C at 8% moisture. There was no cake collapse and were no differences in the secondary structure by FTIR. All formulations were stable at 5°C. High moisture cakes had higher aggregation rates than drier samples if stored above their T_g values. Intermediate moisture vials were more stable to aggregation than dry vials. High moisture samples had increased rates of Asp isomerization at elevated temperatures both above and below their T_g values. Chemical and physical degradation pathways followed Arrhenius kinetics during storage in the glassy state. Only Asp isomerization followed the Arrhenius model above the T_g value. Both chemical and physical stability at T T_g were fitted to Williams-Landel-Ferry (WLF) kinetics. The WLF constants were dependent on the nature of the degradation system and were not characteristic of the solid system. Conclusion. High moisture levels decreased chemical stability of the formulation regardless of whether the protein was in a glassy or rubbery state. In contrast, physical stability was not compromised, and may even be enhanced, by increasing residual moisture if storage is below the T_g value.     

The use of differential scanning calorimetry for the purity verification of pharmaceutical reference standards

Reference standards are routinely used in pharmaceutical industry to determine strength, content, and the quality of drug products, active pharmaceutical ingredients (API), preservatives, antioxidants and excipients. Traditionally, chromatographic techniques such as High Performance Liquid Chromatography (HPLC) and Gas Chromatography (GC) in conjunction with other analytical techniques have been used to determine the purity and strength of a specific lot of a compound for the purpose of qualifying the lot to use as a reference standard. The assigned purity of the reference standard for a wide variety of compounds can be verified using an absolute method such as Differential Scanning Calorimetry (DSC). In this paper, purity of 16 reference standards was determined by DSC and the results were then compared to the purity values that were obtained using HPLC and other analytical techniques. The results indicate that the purity obtained from DSC analysis is comparable to the chromatographic purity for organic compounds that are at least 98% pure. Use of DSC for purity determination is not appropriate if a compound lacks sharp melting point, decomposes in the defined temperature range or exhibits other thermal event(s) which interfere with the melting point of the compound. The use of DSC as an alternative and or complementary method to verify the purity of a compound as part of the pharmaceutical reference standard certification process is discussed.     

Gaining Thermodynamic Insight From Distinct Glass Formation Kinetics of Structurally Similar Organic Compounds

Thermodynamic and kinetic aspects of crystallization of 12 structurally similar organic compounds were investigated from the supercooled liquid state by calorimetric and rheologic measurements. Based on their crystallization behaviors, these compounds were divided into 3 categories: stable glass formers, poor glass formers, and good glass formers with poor stability on reheating. Correlation was sought between thermodynamic quantities and glass formation based on nucleation and crystal growth theories. Larger values of enthalpy of fusion and melting point were found to correlate with poor glass-forming ability. Conversely, lower entropy of fusion was found to correlate with glass formation. Examination of kinetic aspects of glass formation revealed 2 important facets of good glass formers, that is, rapid increase in viscosity on supercooling and high melting point viscosity compared with non-glass formers. A broader relationship was sought between entropy of fusion and glass formation by including several glass formers from literature. Our analysis indicated that good glass formers tend to have an entropy of fusion closer to 0.3 J cm^?3 K^?1. The structural similarity of the compounds in this study provides insights regarding the nature of intermolecular interactions responsible for the observed effect on entropy of fusion, viscosity, and crystallization kinetics.     

用差示扫描量热法测定葡萄糖酸锌的热稳定性

用差示扫描量热法(DSC)测定葡萄糖酸锌的热稳定性,用Kissinger方程和Ozawa方程计算反应活化能,分别为96.9和93.6 kcal·mol~(-1)。     

不同结晶条件下7-ACA晶型结构与质量稳定性研究

本文利用粉末X射线衍射（XRD）、红外光谱法（FT-IR）、拉曼光谱和差热分析（DTA）,对不同结晶条件下得到的四种7-ACA（7－氨基头抱烷酸）样品的晶型结构进行研究,同时也对上述结晶条件下制备的7-ACA产品进行质量稳定性研究;结果表明7-ACA在不同结晶条件下可获得相同晶型结构,且其质量稳定性没有显著性差异。从而说明7-ACA结晶条件较宽松．不同结晶方式能产生相同晶型结构的产品,且质量稳定性一致。     

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.     

盐酸环丙沙星的热稳定性和热分解反应动力学研究

目的:用热分析法分析盐酸环丙沙星的热分解过程及机制。方法:以Al2O3为参比物,在氮气条件下采用差示扫描量热法、热重法和微分热重法分析样品,根据热重曲线数据计算出其特征热分解反应表观活化能(E)、指前因子(A)、反应级数n和pk值。结果:E=101.18kJ.mol-1、lnA=26.96s-、n=1、pk=7.01,常温下药品贮存期为2年。结论:用热分析法研究盐酸环丙沙星等固体药物的热分解过程方法简便,结果可靠。     

Solubilization of Cyclosporine in Topical Ophthalmic Formulations: Preformulation Risk Assessment on a New Solid Form

Owing to the discovery of a less soluble crystalline form (form 2) of cyclosporine (CsA), risks in solubility and physical stability of these formulations need to be revisited. This work focused on understanding the solubility behavior of various CsA forms in different media, including water, castor oil, and selected cosolvent micellar systems. In water, form 2 was approximately 8-9 times less soluble than form 1 (aka. tetragonal dihydrate). In neat nonaqueous solvent, for example, castor oil, form 3 (aka. orthorhombic hydrate) was found to have the lowest solubility and therefore the most stable form. In addition, the solubility-temperature relationship of CsA is complex and solvent-dependent. In aqueous vehicles, retrograde temperature dependence of solubility was observed in aqueous vehicles, that is, the solubility of CsA decreased with temperature, which was attributed to the effect of temperature on the strength of hydrogen bonding interactions; conversely, the solubility of CsA increased with temperature in nonaqueous solvents. In addition, the solubility of these CsA forms was very sensitive to temperature. Temperature-dependent form transformation was also observed in the media studied, with faster form conversion occurring at elevated temperatures. These studies provided key information to support the risk assessment for topical ophthalmic formulation development of CsA.     

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

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

黄体酮的热特性分析

目的:观察黄体酮药物的热特性,并测定其纯度。方法:利用差示扫描量热法(DSC)和导数热重法(DTG)测定黄体酮的熔点、纯度及挥发性物质,在氮气氛下升温速率分别为1.5,10,20℃·min~(-1)。结果:用差示扫描量热法,升温速率为1.5℃·min~(-1),测定黄体酮的熔点为130℃,在程序控温下对其吸热峰进行分析,其纯度为99.8%,与高效液相色谱测定的结果(99.9%)一致。用导数热重法可准确测定其挥发性物质包括水分在内的变化,以及推测其降解历程。结论:该分析法简便、快捷,可测定黄体酮的晶型、水分及纯度,并为研究降解机理及开发新剂型提供参考。     

Thermal insight of mechanically activated bile acid powders

Mechanical activation of pharmaceutical materials presents an important but poorly understood phenomenon of milled molecular crystals. In this work, a strategy was followed in an effort to understand this phenomenon, cryo-milled of both crystalline and amorphous counterpart of bile acids materials were characterized by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). The XRPD results for the 30-min milled crystalline powders displayed a characteristic amorphous halo patterns for all compounds tested. The DSC thermograms exhibited the typical glass transition temperatures (T_g) associated with amorphous but only for two materials. For the remaining four milled compounds, a rather interesting behavior was manifested through a characteristic exothermal bimodal peak. The findings seemed to suggest that the occurrence of this event was not related to the (T_g), but likely to the melting temperature (T_m). The DSC results for the melt-quenched (amorphous) ursodeoxycholic acid after cryo-milling revealed that the material crystallized after the influence of the mechanical stress, and a bimodal peak was also observed similar to that of the cryo-milled crystalline material. It is contemplated that the response of the physical instability of the disordered phase could be explained either by the result of surface crystallization kinetics which is different from that of the bulk crystallization, or by the creation of supersaturated dislocated crystal prior to amorphization.