Solid-State Characterization of Spironolactone 1/3 Hydrate

Spironolactone (SPR) is a poorly water-soluble drug widely used for the treatment of various diseases. The objective of this study was to carry out the preparation and solid-state characterization of SPR 1/3 hydrate. The solid form was generated by an unreported recrystallization process in acetone and characterized for the first time by a combination of X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier-transform infrared spectroscopy (FTIR), equilibrium solubility, and an accelerated stability study. XRD, DSC, and TGA studies revealed that SPR 1/3 hydrated converts completely to form II after heating to 180°C. Solubility studies at 37°C showed that SPR 1/3 hydrate was statistically less soluble than SPR form II in all tested media and that SPR form II partially converts to SPR 1/3 hydrate in aqueous media. Accelerated stability studies demonstrated that both forms were physically and chemically stable up to 6 months (40°C/75% RH). We concluded that contamination of SPR 1/3 hydrate in SPR raw materials is undesirable. Taking this into account we recommend its polymorphic monitoring either in active pharmaceutical ingredients or commercial tablets by solid-state identification/quantification methods (XRD, DSC, TGA, and FTIR). Of these, XRD proved to be the most conclusive and accurate.     

Miniaturized Assay for Solubility and Residual Solid Screening (SORESOS) in Early Drug Development

Purpose The aim was to develop a miniaturized method for solubility and residual solid screening of drug compounds in aqueous and non-aqueous vehicles in early drug development. Methods Different crystal modifications of caffeine, carbamazepine, and piroxicam were added into 96-well filter plates and solubility was determined in 100 μl of 17 pharmaceutical vehicles. After filtration, drug concentration was determined by Ultra Performance Liquid Chromatography™ (UPLC). Residual solid drug in the filter plates was analyzed by high-throughput (HT) transmission X-ray Powder Diffraction (XRPD). Results HT XRPD analysis revealed solid form conversions of all compounds during solubility determination, e.g., formation of hydrates in aqueous vehicles (caffeine, carbamazepine, piroxicam) or conversion of a metastable crystal form to the stable form (caffeine). Drug solubility was strongly dependent on the crystal modifications formed during the solubility assay. Conclusions The new assay allows the simultaneous, small scale screening of drug solubility in various pharmaceutical vehicles and identification of changes in solid form. It is useful for the identification of formulations and formulation options in non-clinical and clinical development.     

长春瑞滨磷脂复合物的制备及其性质研究

目的制备长春瑞滨磷脂复合物,提高药物的脂溶性,以期进一步制备长春瑞滨微粒载药系统。方法采用溶剂挥发法制备长春瑞滨磷脂复合物,以复合率为评价指标进行单因素优化试验。采用差示扫描量热法、X射线衍射法、紫外分光光度法对复合物进行鉴别,并考察复合物的体外溶解性质变化。结果优化条件下制备的磷脂复合物复合率为89.3%～93.7%;差示扫描量热法、X射线衍射法、紫外分光光度法验证了复合物的形成;形成磷脂复合物后,长春瑞滨的脂溶性显著提高。结论制备的长春瑞滨磷脂复合物能显著增加药物的脂溶性,为进一步制备长春瑞滨微粒载药系统奠定基础。     

Lactulose: A Model System to Investigate Solid State Amorphization Induced by Milling

In this article, we show that crystalline lactulose can be amorphized directly in the solid state by mechanical milling. Moreover, compared to similar materials, the amorphization kinetics of lactulose is found to be very rapid and the amorphous state thus obtained appears to be very stable against recrystallization on heating. These features make lactulose a model compound for this type of solid state transformation. The ease of crystalline lactulose to be amorphized on milling is explained by comparing elastic constants of lactulose with those of several other disaccharides. These constants have been determined by molecular dynamics simulations. The article also shows how isothermal dissolution calorimetry can be used effectively for the determination of amorphization kinetics during grinding when the usual characterization techniques (differential scanning calorimetry and powder X-ray diffraction) fail.     

Cyclodextrin and phospholipid complexation in solubility and dissolution enhancement: a critical and meta-analysis

Introduction: Poor solubility and dissolution of drugs are the major challenges in drug formulation and delivery. In order to improve the solubility and dissolution profile of drugs, various methods have been investigated so far. The cyclodextrin (CD) complexation and phospholipid (PL) complexation are among the exhaustively investigated methods employed for more precise improvement of the solubility and dissolution of poorly water-soluble drugs.

Areas covered: The article discusses the CD and PL complexation techniques of solubility and dissolution enhancement. Various studies reporting the CD and PL complexation as the potential approaches to improve the dissolution, absorption and the bioavailability of the drugs have been discussed. The article critically reviews the physicochemical properties of CDs and PLs, eligibility of drugs for both the complexation, thermodynamics of complexation, methods of preparation, characterization, advantages, limitation and the meta-analysis of some studies for both the techniques.

Expert opinion: The CD and PL complexation techniques are very useful in improving solubility and dissolution (and hence the bioavailability) of biopharmaceutical classification system Class II and Class IV drugs. The selection of a particular kind of complexation can be made on the basis of eligibility criteria (of drugs) for the individual techniques, cost, stability and effectiveness of the complexes.     

Freeze-Drying From Organic Co-Solvent Systems,Part 2: Process Modifications to Reduce Residual Solvent Levels and Improve Product Quality Attributes

The use of co-solvent systems can benefit the freeze-drying process and product performance. In this study, cycle designs were applied based on existing recommendations for water-based formulations. Modifications thereof and the influence on the process (e.g., drying times) and product quality attributes (e.g., product appearance, residual solvent) were tested for various cosolvent systems. It was found that fast freezing was associated with the formation of large crystals for 50 mg/g polyvinylpyrrolidone in 40% 1,4-dioxane (w/w), resulting in a 7% reduction of primary drying. The application of high shelf temperatures during primary drying for 50 mg/g polyvinylpyrrolidone in 70% tert-butanol was feasible, resulting in shorter primary drying times but high residual solvent levels (7.7%). Most notable was that the inclusion of an evaporation step after freezing improved the product appearance for low-melting co-solvents (10% ethanol and 10% acetone). No ice or solvent nucleation occurred in the case of 50 mg/g mannitol in 50% N,N-dimethylacetamide during the normal freezing stage. Instead, the solution viscosity significantly increased after cooling to low shelf temperatures, followed by product evaporation (rather than sublimation) during the drying phase and failure to form a product cake after drying. The application of annealing enabled nucleation and sublimation.     

Physical State of Misoprostol in Hydroxypropyl Methylcellulose Films

Scanning electron (SEM) and light microscopy (LM), differential scanning calorimetry (DSC), and dynamic mechanical analysis (DMA) techniques were utilized to determine the miscibility of misoprostol and HPMC in the films with a misoprostol content from 0 to 29%, prepared using ethanol and methylene chloride/methanol (MeCl₂/methanol, 50:50). Transmission infrared (TIR) analysis was used to look for evidence of any interaction between misoprostol and HPMC. The LM and SEM analysis of the ethanol cast films indicated no oil droplets. The DSC thermograms of the films showed no evidence of a –33°C transition, which is characteristic of pure misoprostol. The DMA showed that the glass–rubber transition temperature (T _g) of the pure HPMC was lowered from 163 to 125–130 and 85–87°C in the presence of 10 and 27–28% misoprostol. Based on these results it is suggested that misoprostol is solubilized in HPMC at concentrations up to 29%. The TIR analysis of the films showed no evidence of interaction between misoprostol and HPMC.     

Enhancing the Pharmaceutical Behavior of Nateglinide by Cocrystallization: Physicochemical Assessment of Cocrystal Formation and Informed Use of Differential Scanning Calorimetry for Its Quantitative Characterization

The aim of this study was to synthetize cocrystals of nateglinide, an antidiabetic agent of biopharmaceutics classification system Class IIa, as a strategy to improve both the solubility and the dissolution rate of the drug. Benzamide was selected by a screening procedure as a suitable coformer, and binary mixtures with different compositions were prepared and analyzed by differential scanning calorimetry (DSC). An in-depth analysis of DSC data allowed obtaining both the eutectic mixture and cocrystal compositions. The rationale of such an analysis was highlighted and explained. Cocrystals were prepared by kneading and solvent evaporation. Their formation was proved by DSC and confirmed by X-ray powder diffraction, solid-state nuclear magnetic resonance, and Fourier-transform infrared spectroscopy. The functional groups involved in the interaction leading to cocrystals formation were investigated by spectroscopic techniques. The in vitro dissolution profiles show that cocrystals have definite better pharmaceutical performances than the pure drug.     

Freeze-Drying From Organic Cosolvent Systems,Part 1: Thermal Analysis of Cosolvent-Based Placebo Formulations in the Frozen State

The use of cosolvent systems has been demonstrated to shorten lengthy freeze-drying processes and improve the solubility and stability of certain active pharmaceutical ingredients. The goal of the present study was to evaluate the suitability of 2 thermal characterization techniques, differential scanning calorimetry and freeze-dry microscopy, and to identify an optimal cosolvent system. Binary mixtures of a cosolvent (tert-butanol, dimethyl sulfoxide, 1,4-dioxane, acetone, or ethanol) and water were investigated. Ternary mixtures of frequently used excipients (50 mg/g mannitol, sucrose, glycine, or polyvinylpyrrolidone [PVP]) and a solvent-water system were then analyzed for their thermal properties. PVP presented a particularly high glass transition temperature (T_g′) in 70% tert-butanol at ?17.9°C. Large needle-shaped crystals that have been shown to be associated with improved processability were observed with mannitol and PVP in 40% 1,4-dioxane. A heterogeneous sublimation rate of the solvent and water whose impact on product stability remained unclear was observed with PVP in 40% 1,4-dioxane. Freeze-dry microscopy analysis demonstrated a possible extension of the process time for PVP in 99% dimethyl sulfoxide due to a slowly moving sublimation front. Conceivable negative consequences and the need for special treatment for low-melting cosolvents, such as ethanol and acetone, were predicted and discussed.     

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.     

Physical Aging of Progesterone-Loaded Poly(D,L,-lactide-co-glycolide) Microspheres

Purpose. To study the interactions between a polymeric matrix and a drug during storage at a temperature lower than the glass transition temperature of the polymers. Methods. Poly(lactide-co-glycolide) microspheres loaded with different progesterone ratios were stored at 4, 20 and 40°C. DSC-scans were recorded at regular intervals, depending on the storage temperature. Results. The physical aging of the polymeric matrix, as monitored by the amplitude of the endotherm associated with the glass transition, is slowed down by crystalline progesterone. The development of the progesterone polymorphic depends on the interface/volume ratio of the crystals. Conclusions. For polymeric drug delivery systems, the determination of all studies parameters must take into account an effect of dispersed drugs which are more sensitive as the storage temperature is lower than the glass transition temperature of the matrix.     

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.     

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.     

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。     

Formation of the Racemic Compound of Ephedrine Base from a Physical Mixture of Its Enantiomers in the Solid,Liquid, Solution,or Vapor State

Physical mixtures (conglomerates) of the two enantiomers of ephedrine base, each containing 0.5% (w/w) of water, were observed to be converted to the 1:1 racemic compound in the solid, liquid, solution, or vapor state. From a geometrically mixed racemic conglomerate of particle size 250–300 µm (50–60 mesh), the formation of the racemic compound follows second-order kinetics (first order with respect to each enantiomer), with a rate constant of 392 mol^–1 hr^–1 at 22°C. The reaction appears to proceed via the vapor phase as indicated by the growth of the crystals of the racemic compound between diametrically separated crystals of the two enantiomers in a glass petri dish. The observed kinetics of conversion in the solid state are explained by a homogeneous reaction model via the vapor and/or liquid states. Formation of the racemic compound from the crystals of ephedrine enantiomers in the solution state may explain why Schmidt et al. (Pharm. Res. 5:391–395, 1988) observed a consistently lower aqueous solubility of the mixture than of the pure enantiomers. The solid phase in equilibrium with the solution at the end of the experiment was found to be the racemic compound, whose melting point and heat of fusion are higher than those of the enantiomers. An association reaction, of measurable rate, between the opposite enantiomers in a binary mixture in the solid, liquid, solution, or vapor state to form the racemic compound may be more common than is generally realized.     

土霉素及其盐酸盐的热特征

用差示扫描量热法 (DSC)和导数热重法 (DTG)测定土霉素及其盐酸盐的热特征 ,包括熔点、多晶型、水分、分解点温度和热焓值。结果显示土霉素与对照品热特征一致。盐酸土霉素熔融分解过程无转晶变化。     

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.     

基于理化性质的枸橼酸托法替布处方前研究

目的 考察枸橼酸托法替布理化性质,为其制剂处方、工艺设计、包装和储藏等提供理论依据。方法 采用HPLC测定药物在不同pH缓冲液及水中的平衡溶解度、脂水分配系数(P)及润湿性;对药物进行影响因素试验;测定药物的粒度、粒度分布、红外光谱(FTIR)、X-射线衍射图谱(XRD)、差示扫描量热图谱(DSC)和扫描电镜图谱(SEM)。结果 枸橼酸托法替布在pH 1.0~8.0的缓冲液及水中的平衡溶解度为0.183 4~22.594 1 mg·mL^-1,属高溶解性药物,其中在pH 1.0缓冲液中的平衡溶解度最大;在上述各介质中,lgP为-1.34~1.28,属低渗透性药物,其中在pH 3.6缓冲液中的lgP最大;在上述各介质中,接触角均<90°,均易于被润湿;枸橼酸托法替布在高温、高湿及强光照射下均较为稳定;平均粒径为(29.85±0.17)µm;XRD、DSC及SEM结果均表明枸橼酸托法替布为结晶性药物,熔点为210 ℃;FTIR结果表明,枸橼酸托法替布在3 375.44,3 134.51,1 732.54,1 711.78,1 625.24,1 551.03,1 529.52,1 473.76,1 448.28,1 409.48,1 348.17,1 213.59,1 170.22,1 115.37,1 077.68,1 023.87,916.97,846.38,775.66,741.84,703.42,603.15,444.07 cm^-1有较强的红外特征峰。结论 枸橼酸托法替布为BCSⅢ类药物,宜设计成胃内滞留型给药系统,有利于药物在上消化道溶解与吸收,以提高生物利用度;本研究使用的枸橼酸托法替布为稳定的结晶性药物,可满足一般制剂生产、包装、贮藏等要求。     

Crystallization of Cyclophosphamide Monohydrate During Lyophilization

The purpose of this study was to investigate the phase behavior of cyclophosphamide (CPA) during various stages of lyophilization, with special emphasis on obtaining crystalline CPA monohydrate (CPA-MH) in the lyophilized product. Subambient differential scanning calorimetry and low-temperature X-ray diffractometry (LTXRD) were used to study the phase behavior of CPA solution (3.7% w/v). In situ lyophilization in LTXRD chamber was used to monitor the phase transitions occurring during the drying stages. Finally, the implications of these findings were confirmed by freeze-drying the aqueous solution in a laboratory-scale freeze-dryer. The results suggested that CPA remains amorphous during freeze concentration, with a T_g' of ?50°C. However, its crystallization as CPA-MH can be induced by annealing the frozen solution between ?5°C and ?10°C. In situ lyophilization in LTXRD showed that the CPA-MH crystallized during annealing, rapidly dehydrated during primary drying, thereby causing structural collapse. The dehydration of CPA-MH can be prevented by lowering the escaping tendency of water molecules from the crystal lattice of CPA-MH by maintaining the chamber pressure to 300, 400, or 500 mTorr. This study highlights the relationship of process parameters used during lyophilization with the solid form of lyophilized CPA.