西咪替丁的晶型研究

目的：建立西咪替丁晶型的测定方法,并对国内西咪替丁原料的晶型进行考察：方法：差示扫描量热（DSC）法,红外光谱法（IR）及X射线衍射（X－ray)法。结果：国内不同厂家生产的西咪替丁原料晶型不同,有A晶型,B晶型和混合晶型。结论：西咪替丁晶型可以采用DSC法,IR法及X－ray法测定,DSC法简便易行且可进行粗略定量。     

盐酸美西律多晶型研究

目的：研究盐酸美西律的多晶型特征。方法：采用差示扫描量热法、红外光谱分析法和X—ray法，对盐酸美西律多晶型进行了初步研究。结果：盐酸美西律原料有多晶型现象，样品经过溶剂处理和热处理后均可获得稳定晶型。结论：获得了盐酸美西律多晶型相关的热力学数据、红外光谱和X—ray特征，为盐酸美西律对照品及其原料和制剂的质量标准提供了依据。     

那格列奈的新晶型

目的　确证降糖药那格列奈另一种新的晶型结构,称为S型。给出X射线衍射、红外图谱和相关数据。方法　用X射线粉末衍射、红外光谱、元素分析和差示扫描量热法作物相分析。结果　S型那格列奈有与文献报道的H型、B型完全不同的晶型。mp 172.04℃。结论　S型那格列奈是一种新的晶型     

阿戈美拉汀的多晶型研究

目的研究阿戈美拉汀的多晶型特征。方法通过平衡溶解度测定、差示扫描量热分析(DSC)、红外光谱(IR)、粉末X射线衍射(PXRD)谱等鉴定阿戈美拉汀多的晶型,并考察其室温放置的稳定性。结果获得Ⅰ～Ⅳ型阿戈美拉汀。利用DSC或PXRD分析可区分4种晶型。结论不同晶型阿戈美拉汀的理化性质有明显差异。Ⅱ型阿戈美拉汀最稳定,Ⅰ、Ⅲ、Ⅳ型稳定性较差。     

普卢利沙星3种晶型的制备、表征与稳定性研究

目的 研究普卢利沙星的多晶型特征,为该药晶型杂质成分的质量控制提供科学依据。方法 制备了普卢利沙星的3种晶型（晶型Ⅰ、晶型Ⅱ和晶型Ⅲ）,采用粉末X射线衍射法、红外光谱法、差示扫描量热分析、拉曼光谱法对普卢利沙星3种晶型进行了表征分析,并通过混悬实验探索3种晶型之间的转化规律及稳定性关系。结果 粉末X射线衍射法、红外光谱法、差示扫描量热分析、拉曼光谱法均能有效区分普卢利沙星的3种晶型,晶型间的稳定性关系为晶型Ⅰ>晶型Ⅱ>晶型Ⅲ。结论 本实验建立的分析方法为普卢利沙星晶型控制标准的制定提供依据。     

酒石酸唑吡坦原料药的多晶型问题研究

采用红外光谱、差示扫描量热法和粉末X射线衍射技术等研究酒石酸唑吡坦原料药的多晶型问题。采用三种方法得到的图谱均显示酒石酸唑吡坦原料药存在多晶型问题,且不同企业生产的样品混晶比例存在一定差异。     

九里香叶总黄酮-羟丙基-β-环糊精包合物的制备、鉴定和热力学稳定性研究

目的制备和鉴定九里香叶总黄酮-羟丙基-β-环糊精包合物,并考察九里香叶总黄酮和羟丙基-β-环糊精之间的包合摩尔比及包合过程的热力学常数。方法采用溶液-搅拌法制备九里香叶总黄酮-羟丙基-β-环糊精包合物,采用差示扫描量热法、X射线衍射法和红外光谱法对包合物进行鉴定,通过表观溶解度法考察包合物中主客分子之间的包合摩尔比及包合过程的热力学常数。结果 25,35,45℃时九里香叶总黄酮和羟丙基-β-环糊精能形成1∶1摩尔比包合物,相溶解度图呈AL型,包合过程为放热反应。结论九里香叶总黄酮与羟丙基-β-环糊精能自发地形成1∶1摩尔比包合物,从而显著提高九里香叶总黄酮在水中的溶解度。     

九里香叶总黄酮-羟丙基-β-环糊精包合物的制备、鉴定和热力学稳定性研究

目的 制备和鉴定九里香叶总黄酮-羟丙基-β-环糊精包合物,并考察九里香叶总黄酮和羟丙基-β-环糊精之间的包合摩尔比及包合过程的热力学常数。方法 采用溶液-搅拌法制备九里香叶总黄酮-羟丙基-β-环糊精包合物,采用差示扫描量热法、X射线衍射法和红外光谱法对包合物进行鉴定,通过表观溶解度法考察包合物中主客分子之间的包合摩尔比及包合过程的热力学常数。结果 25,35,45 ℃时九里香叶总黄酮和羟丙基-β-环糊精能形成1∶1 摩尔比包合物,相溶解度图呈AL型,包合过程为放热反应。结论 九里香叶总黄酮与羟丙基-β-环糊精能自发地形成1∶1 摩尔比包合物,从而显著提高九里香叶总黄酮在水中的溶解度。     

异烟肼缓释固体分散体的制备及其体外评价

目的制备异烟肼缓释固体分散体,考察其分散状态和体外溶出速率。方法以水不溶性聚合物乙基纤维素为载体,用溶剂法制备异烟肼缓释固体分散体。采用X射线衍射法、差示扫描量热法和红外光谱法鉴别药物在固体分散体中的存在状态,并对其体外释放情况进行研究。结果 X射线衍射法表明异烟肼在固体分散体中有一部分是以分子状态分散,而另一部分可能以微晶体状态分散;差示扫描量热法表明所制备的缓释固体分散体中不存在药物结晶;红外光谱法结果表明异烟肼与乙基纤维素未发生化学反应;溶出度试验结果表明其具有良好的缓释效果。结论采用溶剂法制备的异烟肼缓释固体分散体可以使药物达到高度分散状态,制备的异烟肼缓释固体分散体具有较好的缓释效果。     

Crystal structure of neotame anhydrate polymorph G

Purpose. To determine the crystal structure of the neotame anhydrate polymorph G and to evaluate X-ray powder diffractometry (XRPD) with molecular modeling as an alternative method for determining the crystal structure of this conformationally flexible dipeptide. Methods. The crystal structure of polymorph G was determined by single crystal X-ray crystallography (SCXRD) and also from the X-ray powder diffraction (XRPD) pattern using molecular modeling (Cerius² , Powder Solve module). Results. From SCXRD, polymorph G crystals are orthorhombic with space group of P2₁2₁2₁ with Z = 4, unit cell constants: a = 5.5999(4), b = 11.8921(8), c = 30.917(2) Å, and one neotame molecule per asymmetric unit. The XRPD pattern of polymorph G, analyzed by Cerius² software, led to the same P2₁2₁2₁ space group and almost identical unit cell dimensions. However, with 13 rigid bodies defined, Cerius² gives a conformation of the neotame molecule, which is different from that determined by SCXRD. Conclusions. For neotame anhydrate polymorph G, the unit cell dimensions calculated from XRPD were almost identical to those determined by SCXRD. However, the crystal structure determined by XRPD closely resembled that determined by SCXRD, only when the correct conformation of the neotame molecule had been chosen before detailed analysis of the XRPD pattern.     

Pushing the Limits of Molecular Crystal Structure Determination From Powder Diffraction Data in High-Throughput Chemical Environments

Crystal structure determination from powder diffraction data (SDPD) using the DASH software package is evaluated for data recorded using transmission capillary, transmission flat plate, and reflection flat plate geometries on a selection of pharmaceutical compounds. We show that transmission capillary geometry remains the best option when crystal structure determination is the primary consideration and, as expected, reflection flat plate geometry is not recommended for SDPD because of preferred orientation effects. However, the quality of crystal structures obtained from transmission plate instruments can be excellent, and the convenience factor for sample preparation, throughput, and retrieval is higher than that of transmission capillary instruments. Indeed, it is possible to solve crystal structures within an hour of a polycrystalline sample arriving in the laboratory, which has clear implications for making small-molecule crystal structures more routinely available to the practicing laboratory medicinal chemist. With appropriate modifications to crystal structure determination software, it can be imagined that SDPD could become a rapid turn-around walk-up analytical service in high-throughput chemical environments.     

磷霉素钙的晶型稳定性研究

目的 对磷霉素钙晶型稳定性进行研究。方法 将磷霉素钙分别置于对应环境中,制备样品后进行粉末X射线衍射（powder X-ray diffraction,PXRD）、差示扫描量热法分析（differential scanning calorimetry,DSC）、电镜扫描（scanning electron microscopy,SEM）以及热解重量分析（thermogravimetric analysis,TGA）,对磷霉素钙晶型进行表征。结果 磷霉素钙存在结晶型和无定型2种晶型,结晶型磷霉素钙在相对湿度（relative humidity,RH）92.5%放置30 d、150℃以下加热2 h,晶型稳定。结论 结晶型磷霉素钙原料晶型稳定,与参比制剂一致,可以满足湿法制粒、流化床制粒对湿度和温度的要求,在一致性评价中,应当选择结晶型磷霉素钙作为制剂原料。     

Crystallization Behavior of Mannitol in Frozen Aqueous Solutions

Purpose. To study the effect of cooling rate, the influence of phosphate buffers and polyvinylpyrrolidone (PVP) on the crystallization behavior of mannitol in frozen aqueous solutions. Methods. Low-temperature differential scanning calorimetry and powder X-ray diffractometry were used to characterize the frozen solutions. Results. Rapid cooling (20°C/min) inhibited mannitol crystallization, whereas at slower cooling rates (10°C and 5°C/min) partial crystallization was observed. The amorphous freeze-concentrate was characterized by two glass transitions at -32°C and -25°C. When the frozen solutions were heated past the two glass transition temperatures, the solute crystallized as mannitol hydrate. An increase in the concentration of PVP increased the induction time for the crystallization of mannitol hydrate. At concentrations of 100 mM, the buffer salts significantly inhibited mannitol crystallization. Conclusions. The crystallization behavior of mannitol in frozen solutions was influenced by the cooling rate and the presence of phosphate buffers and PVP.     

Synthesis,Characterization, and Crystal Chemistry of Tasimelteon,a Melatonin Agonist,in Its Anhydrous and Hemihydrate Forms

Two crystalline forms of tasimelteon, a drug approved by the U.S. Food and Drug Administration for the treatment of non-24-h sleep-wake disorder, have been studied by single crystal and powder diffraction analyses, thermogravimetric analysis, differential scanning calorimetry, spectroscopic, and optical methods. The synthetic method forming tasimelteon is described in detail, with its full analytical, spectroscopic, and enantiopurity characterization. Solid tasimelteon hemihydrate, C₁₅H₁₉NO₂·0.5H₂O, is tetragonal with a = b = 7.3573(2) Å, c = 52.062(2) Å, V = 2818.1(2) ų; Z = 8. Its crystal structure has been solved and refined in the P4₃2₁2 space group, showing the occurrence of polymeric (H-bonded) slabs, thanks to the presence of water molecule (O_W) tetrahedrally linked to 4 distinct tasimelteon molecules in a N₂(O_W)O₂ fashion. The anhydrous form of tasimelteon, C₁₅H₁₉NO₂, crystallizes in the monoclinic P2₁ space group, with a = 11.130(4), b = 4.907(2), c = 12.230(6) Å, β = 91.03(3)°, V = 667.8(5) ų; Z = 2. Thanks to the availability of good-quality specimens, the structure of the latter phase was solved by conventional single-crystal diffraction analysis, showing short intermolecular C=O^…H–N interactions between (translationally related) tasimelteon molecules, forming, in the crystal, well-defined chains running along the b axis. The morphology of the 2 crystal forms has been analyzed by the means of optical microscopy and particle size distribution analysis. Worthy of note, the newly determined crystal structures enable the successful usage of full-pattern matching X-ray-based quantitative analyses of batches of industrial interest, in search for contamination or phase stability issues.     

Phase Transitions of Glycine in Frozen Aqueous Solutions and During Freeze-Drying

Purpose. To study the solid-state and phase transitions of glycine, (i) in frozen aqueous solutions, and (ii) during freeze-drying. Methods. X-ray powder diffractometry (XRD) and differential scanning calorimetry (DSC) were used to analyze the frozen systems. In situ freeze-drying in the sample chamber of the diffractometer enabled characterization of phase transitions during freeze-drying. Results. Transitions in frozen systems. Rapid (20°C/min) or slow (2°C/min) cooling of aqueous solutions of glycine (15% w/w) to –70°C resulted in crystallization of -glycine. Annealing at –10°C led to an increase in the amount of the crystalline phase. When quench-cooled by immersing in liquid nitrogen, glycine formed an amorphous freeze-concentrate. On heating, crystallization of an unidentified phase of glycine occurred at \-65°C which disappeared at –55°C, and the peaks of -glycine appeared. Annealing caused a transition of - to the - form. The extent of this conversion was a function of the annealing temperature. Slower cooling rates and annealing in frozen solutions increased the crystalline -glycine content in the lyophile. Freeze-drying of quench-cooled solutions led to the formation of -glycine during primary drying resulting in a lyophile consisting of a mixture of - and -glycine. The primary drying temperature as well as the initial solute concentration significantly influenced the solid-state of freeze-dried glycine only in quench-cooled systems. Conclusions. The cooling rate, annealing conditions and the primary drying temperature influenced the solid-state composition of freeze-dried glycine.     

The Effect of Additives on the Crystallization of Cefazolin Sodium During Freeze-Drying

Purpose. To monitor the phase transitions during freeze-drying of cefazolin sodium (I) as a function of process and formulation variables. Methods. Aqueous solutions of I were frozen under controlled conditions in the sample chamber of a variable temperature X-ray powder diffractometer (XRD). The instrument was modified so that the chamber could be evacuated and the samples dried under reduced pressures. Thus, the entire freeze-drying process was carried out in the XRD holder with real time monitoring of the phase transitions during the different stages of freeze-drying. Results. When aqueous solutions of cefazolin sodium (10% w/w) were cooled to -40°C, the XRD pattern revealed only the crystallization of ice. Annealing the frozen sample led to the crystallization of I as the pentahydrate. Differential scanning calorimetry revealed that the presence of isopropyl alcohol (IPA) (5% w/w) led to a decrease in the Tg, the glass transition temperature of the system, and lowered the temperature of crystallization. The crystallization was studied at -8 and at -15°C in the XRD, and, as expected, more rapid crystallization was observed at the higher temperature. Primary drying at -8°C led to the dehydration of the pentahydrate, resulting in a poorly crystalline product. Again, XRD permitted real time monitoring of the decrease in intensities of some characteristic peaks of the pentahydrate. The in situ XRD technique also enabled us to study the effects of processing conditions (different primary and secondary drying temperatures) and crystalline bulking agents on the solid-state of I in the lyophile. When I was lyophilized using mannitol or glycine as an additive, without an annealing step, the drug was X-ray amorphous although the additive crystallized. When annealed and freeze-dried, I remained crystalline in the presence of glycine but not in the presence of mannitol. Conclusions. The in situ XRD technique has enabled us to characterize the phase transitions during freeze-drying of cefazolin sodium in multicomponent systems.     

Crystal structure of L-lysyl-L-glutamic acid dihydrate

L-Lysyl-L-glutamic acid dihydrate, C₁₁N₃O₅H₂₁·2H₂O, crystallizes in the monoclinic space group P2₁ with a = 12.474(2), b = 5.020(1), c = 13.157(2) Å, β= 114.69(1)° and Z = 2. The crystal structure was solved by direct methods and refined to an R value of 0.037 using full matrix least-squares method. The molecule exists as a double zwitterion with both the amino and carboxyl groups ionised. The peptide has a folded conformation with its Lys residue trans and Glu residue gauche^?gauche⁺. The side chains of the Lys and Glu residues correspond to all trans and folded (g^?g^?g^?) conformations respectively. The terminal carboxyl group forms hydrogen bonds with the ξ-amino group of the lysine side chain. The head-to-tail interaction often seen in peptide crystals is absent in the present structure. In the extended crystal structure water molecules form channels along the b direction and are enclosed within helically arranged hydrogen bonds formed by the lysine side chain and the peptide backbone.     

Influence of polybutylcyanoacrylate nanoparticles and liposomes on the efficacy and toxicity of the anticancer drug mitoxantrone in murine tumour models

Abstract

Polybutylcyanoacrylate (PBCA) nanoparticles were prepared and loaded with mitoxantrone, a highly effective anticancer drug. The proportion of mitoxantrone bound to the particles was analysed to be about 15 per cent of the initial drug concentration with the incorporation method and about 8 per cent with the adsorption method. Selected nanoparticle formulations were tested in leukaemia-or melanoma-bearing mice after intravenous injection. Efficacy and toxicity of mitoxantrone nanoparticles were compared with a drug solution and with a mitoxantrone-liposome formulation (small unilamellar vesicles with a negative surface charge). Furthermore, influence of an additional coating surfactant, poloxamine 1508, which has been shown to change body distribution of other polymeric nanoparticles, was investigated. It was shown that PBCA nanoparticles and liposomes influenced the efficacy of mitoxantrone in cancer therapy differently: liposomes prolonged survival time in P388 leukaemia, whereas nanoparticles led to a significant tumour volume reduction at the B16 melanoma. Neither nanoparticles nor liposomes were able to reduce the toxic side-effects caused by mitoxantrone, namely leucocytopenia. A slight additional influence of the coating surfactant was observed with only one preparation.     

Physicochemical Characterization of High- and Low-Melting Phenylephrine Oxazolidines

Phenylephrine oxazolidine is a new prodrug of phenylephrine developed for improving ocular absorption and reducing systemic side effects. In the present study, high- and low-melting phenylephrine oxazolidines (HMP and LMP) were characterized in terms of their stereochemistry and crystal properties. It was found that the molecular configuration of the prodrug in the crystals of either HMP or LMP is identical (5R/2R). The two crystals were shown to have the same IR spectra and X-ray diffraction patterns but different crystal habits, thermal properties, solubilities and intrinsic dissolution rates. Single crystal X-ray structure analysis indicates that crystals of both HMP and LMP are orthorhombic and belong to the P2₁2₁2₁ space group with four molecules in a unit cell (a = 20.697 , b = 7.065 , and c = 9.304 ). The molecules in the crystal are held together by an intermolecular hydrogen bonding interaction between N(3) and O(13). The different physical properties observed for LMP result from crystal imperfections caused by the presence of trace amounts (often at levels <0.5%) of an unidentified, structurally related synthetic impurity which can be dispersed in the pro-drug. It was observed that both HMP and LMP can sustain thermal and mechanical treatment in the solid state. However, LMP was partially converted to HMP when suspended in certain solvents.