Physicochemical and mechanical properties of carbamazepine cocrystals with saccharin

The aim of present research was to investigate the physicochemical, mechanical properties, and stability characteristics of cocrystal of carbamazepine (CBZ) using saccharin (SAC) as a coformer. The cocrystals were prepared by solubility method and characterized by pH-solubility profile, intrinsic dissolution by static disk method, and surface morphology by scanning electron microscopy (SEM), crystallinity by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD), and mechanical properties by Heckel analysis. Stability of the cocrystals were assessed by storing them at 60 (°)C for two weeks, 25 (°)C/60%RH, 40 (°)C/75%RH and 40 (°)C/94%RH for one month and compared with the stability of CBZ. The solubility profile of cocrystal was similar to CBZ. The cocrystal and CBZ have shown the same stability profile at all the conditions of studies except at 40 (°)C/94%RH. Unlike the CBZ, cocrystal was stable against dihydrate transformation. The compacts of cocrystal have a greater tensile strength and more compressibility. The Heckel analysis suggested that plastic deformation started at low compression pressure in the cocrystal than CBZ. In summary, the cocrystal form of carbamazepine provides another avenue for product development which is more stable than the parent drug.     

Qualitative in situ analysis of multiple solid-state forms using spectroscopy and partial least squares discriminant modeling

This study used in situ spectroscopy to reveal the multiple solid-state forms that appear during isothermal dehydration. Hydrate forms of piroxicam and carbamazepine (CBZ) were investigated on hot-stage at different temperatures using near-infrared (NIR) and Raman spectroscopy combined with multivariate modeling. Variable temperature X-ray powder diffraction, differential scanning calorimetry, thermogravimetric analysis, and Karl Fisher titrimetry were used as reference methods. Partial least squares discriminant analysis (PLS-DA) was performed to qualitatively evaluate the phase transition. It was shown that the constructed PLS-DA models, where spectral differences were directly correlated to solid-state modifications, enabled differentiation between the multiple forms. Qualitative analysis revealed that during dehydration, hydrates, such as CBZ dihydrate, may go through several solid-state forms, which must be considered in quantitative model construction. This study demonstrates that in situ analysis can be used to monitor the dehydration and reveal associated solid-state forms prior to quantification. The utility of the complementary spectroscopic techniques, NIR and Raman, have been shown.     

Preparation and characterisation of a new insoluble polymorphic form of glibenclamide

A crystalline form of glibenclamide, with higher melting point (218 degrees C) and lower solubility in simulated gastric and intestinal fluids, was arisen during an attempt to elucidate transitional phases by melting, cooling and reheating. The new form was obtained from the glassy state, by applying sublimation at 130-160 degrees C and was characterised by differential scanning calorimetry (DSC), infrared (IR) spectroscopy, scanning electron microscopy (SEM), hot-stage microscopy (HSM), X-ray powder diffraction (XRD) and solubility studies. Formation of the new crystal form is considered as reason of reduction in dissolution and bioavailability of tablets.     

Probing Influence of Solvent on Polymorphic Transformation of Carbamazepine Using Electrospray Technology

Purpose

The objective of the current work was to investigate the influence of electrospray technology using various solvents on polymorphic transformations of carbamazepine (CBZ). CBZ was taken as a model drug for electrospray crystallization owing to its well investigated polymorphic forms.

Methods

Saturated CBZ solutions (methanol, ethanol, and 2-propanol) were electrosprayed at 20 kV to obtain CBZ crystals. The electrosprayed crystals from methanol (MCBZ), ethanol (ECBZ), and 2-propanol (PCBZ) were characterized by powder X-ray diffractometry, Fourier-transform infrared spectroscopy, differential scanning calorimetry, scanning electron microscopy, equilibrium solubility, intrinsic dissolution rate, and stability study.

Results

MCBZ exhibited mixture of form I and II of CBZ, whereas mixture of form I, II, and III of CBZ was observed in case of ECBZ. Further, PCBZ contained mixture of form II, III, and IV of CBZ. The order in which reduction in saturation solubility and intrinsic dissolution rate was observed, it can be represented as MCBZ > PCBZ > ECBZ > unprocessed CBZ. Electrospray technology induced polymorphic transformations in CBZ crystals. The said polymorphic transformations were influenced by solvent properties along with an electric charge.

Conclusion

Thus electrospray crystallization, a continuous pharmaceutical manufacturing technique, can serve as an alternative for crystallization of API with an ability to modify their physicochemical properties.

     

Olanzapine Solvates

Olanzapine was crystallized from 12 organic solvents alone or in mixture, by cooling in the freezer, by slow evaporation of the solvent, or by suspending olanzapine powder for some time in the solvent. All the samples thus obtained were examined by thermal analysis (differential scanning calorimetry—DSC and thermogravimetry—TG) to certify the formation of a solvate, the presence of polymorph (form 1 or 2) in the desolvated olanzapine, comparing the different profile of the thermograms, and to calculate the stoichiometry of the possible solvate. According to the DSC thermogram, the solvents can be divided into four classes: those that do not form solvates and leave olanzapine form 1 (ethyl acetate, toluene, diethyl ether, and acetone); those that form solvate and leave form 1 of olanzapine after desolvation (methanol, 1- and 2-propanol); those that after desolvation of the solvate show a polymorph transition in the thermogram indicating the presence of form 2 of olanzapine (ethanol); other solvents (tetrahydrofuran, chloroform, acetonitrile) give solvate thermograms, where this last thermal trace is only poorly evident. With few exceptions, each solvent forms solvate both when pure and in mixture (10%, v/v, in ethyl acetate). Methanol monosolvate displays complex thermogram and thermogravimetric desolvation profiles, depending on the crystallization experimental conditions, used to prepare the solvates. Dichloromethane solvate was found by X-ray diffraction analysis to be amorphous and, on heating during DSC analysis, allowed the crystallization of both form 1 and 2, with different weight ratio, according to the experimental conditions of the solvate preparation.     

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.     

Physicochemical characterization of solid dispersions of carbamazepine formulated by supercritical carbon dioxide and conventional solvent evaporation method

Solid dispersions of carbamazepine (CBZ) were formulated by supercritical fluid processing (SCP) and conventional solvent evaporation in polyethylene glycol (PEG) 8000 with either Gelucire 44/14 or vitamin E TPGS NF (d-alpha-tocopheryl PEG 1000 succinate). Formulations were evaluated by dissolution, scanning electron microscopy, powder X-ray diffraction, and differential scanning calorimetry, and excipient cytotoxicity in Caco-2 cells by MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt] assay. CBZ release was enhanced from supercritical fluid-treated CBZ and the CBZ/PEG 8000 (1:5), CBZ/PEG 8000/TPGS or Gelucire 44/14 (1:4:1) solid dispersions. The radically altered morphologies of SCP samples seen by scanning electron microscopy suggested polymorphic change that was confirmed by the X-ray diffraction and differential scanning calorimetry. Disappearance of the characteristic CBZ melting peak indicated that CBZ was dissolved inside the carrier system. Polymorphic change of CBZ during SCP led to faster dissolution. Therefore, SCP provides advantages over solid dispersions prepared by conventional processes.     

In vitro and in vivo evaluation of novel immediate release carbamazepine tablets: complexation with hydroxypropyl-β-cyclodextrin in the presence of HPMC

Carbamazepine (CBZ)-hydroxypropyl-β-cyclodextrin (HP-β-CD) complex in the presence of HPMC was prepared and characterized by differential scanning calorimetry (DSC) and X-ray diffractometer intended for improving the dissolution rate of CBZ. The phase-solubility method was used to investigate the effect of HP-β-CD and HPMC on the solubility of CBZ. Tablets of the resulting complex were prepared using direct compression method and the bioavailability was evaluated in beagle dogs using a UPLC/MS/MS method. The results showed solubility of CBZ was increased up to 95 times by complexation with HP-β-CD in the presence of 0.1% HPMC. The results of DSC and X-ray diffraction proved a formation of complex between CBZ and HP-β-CD. Dissolution rate of CBZ was notably improved from complex tablets with more than 97.39% released within 10 min; whereas for the commercial tablets, around 60% was released within 30 min. Using commercial tablets as the reference formulation, the bioavailability of complex tablets was considerably increased by 1.5-fold (P<0.05) and T(max) was reduced to 0.88 h compared with 1.25 h for commercial tablets. Furthermore, a lower inter-subject variability (49.9%) was observed compared with that of the commercial tablets (39.7%). It is evident from the results herein that complexation with HP-β-CD in the presence of HPMC is a feasible way to prepare a rapidly acting and better absorbed CBZ oral product.     

The polymorphism of sulphathiazole

The existence of two species of the low temperature form of sulphathiazole, postulated by Moustafa & Carless (1969) and by Shenouda (1970), has been confirmed. Contrary to the opinions of these workers it is concluded that these are two distinct forms having different lattice structures which give rise to distinguishable X-ray diffraction patterns and infrared spectra. The fact that commercial samples frequently contain both forms casts doubt on the validity of previous solubility measurements and on the use of differential scanning calorimetry as an assay procedure for the low temperature form.     

Influence of Simulated Gastrointestinal Fluids on Polymorphic Behavior of Anhydrous Carbamazepine Form III and Biopharmaceutical Relevance

The dissolution behavior and bioavailability of carbamazepine (CBZ) is rate-limited by formation of carbamazepine dihydrate (CBZ-D) in dissolution fluids. The present investigation involves formation and biopharmaceutical evaluation of CBZ-D obtained from simulated gastrointestinal fluids. The results obtained from solubility studies revealed that formation of CBZ-D was pH-dependent. The minimum solubility of 115 ± 1.7 mg/L obtained with simulated gastric fluid without pepsin indicates that the strongly acidic pH favors formation of CBZ-D and it was confirmed by the powder X-ray diffractography. Differential scanning calorimetry thermograms of samples revealed formation of CBZ-D and subsequent transition of CBZ form I. The percentage relative crystallinty for dihydrate was found to be 77.51%. Triton X present in fasted-state simulated gastric fluid (FaSSGF) increased the extent of crystallinty in dissolution media upto 86.50%. However, CBZ-D obtained from FaSSGF showed highest solubility of 335.36 ± 4.813 mg/L and dissolution of 36.74% in 60 min. This may be due to presence of surfactant on the surface of CBZ-D. The linear correlation was established between pH of simulated gastrointestinal fluids and percentage relative crystallinty with a correlation coefficient of 0.9904. CBZ form I had a better dissolution profile than any of the other polymorphs. Stabilization of CBZ form I in in vitro and in vivo conditions using pharmaceutical polymers in dosage form may bring better clinical outcomes than present-day therapies.     

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.     

Characterization,quantification and stability of differently prepared amorphous forms of some oral hypoglycaemic agents

The study deals with the investigation of possible differences induced in the physicochemical properties within the amorphous forms prepared by different methods. Enthalpy of solution measured by solution calorimetry was utilized to highlight the differences prevailing within the amorphous forms and to determine the percentage of amorphous content. Emphasis is laid on the quantification and physical stability of these forms. Amorphization was induced in poorly water-soluble oral hypoglycaemic agents (repaglinide, gliclazide and glipizide), by quench cooling, vaporization under reduced pressure and lyophilization. The amorphous nature was evident from a halo pattern in powder X-ray diffraction. A glass transition event is evident in differential scanning calorimetry thermograms of the amorphous forms of the three drugs. As expected, the amorphous forms show improvement in solubility and dissolution profiles. On subjecting these amorphous forms to different relative humidities at 25°C for three months and subsequent analysis showed that amorphous form of repaglinide prepared by quench cooling is most stable and has the potential to be formulated without any additive while amorphous form of gliclazide tends to devitrify pointing towards its unstable nature.     

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.     

Amphiphilic gels as a potential carrier for topical drug delivery

This study involves development of amphiphilic gels consisting solely of nonionic surfactants bearing cyclosporine and characterized for microstructure, gelation temperature, and in vitro drug release into dermis. The formulation is nonirritant and suitable for topical application. Gels consisting of cyclosporine were prepared using different methods by mixing the solid gelator (sorbitan or glyceryl fatty acid esters) and the liquid phase (liquid sorbitan esters or polysorbates) and heating them at 60°C to form a clear isotropic sol phase, and cooling this sol phase to form an opaque semisolid at room temperature. Gel microstructure was examined by phase contrast microscopy while gelation temperatures were measured by melting point apparatus and differential scanning calorimetry. These amphiphilic gels were evaluated in vitro for topical as well as transdermal delivery using rat skin mounted in a Franz diffusion cell. Gel microstructures consisted mainly of clusters of tubules of gelator molecules that had aggregated upon cooling of the sol phase, forming a 3D network throughout the continuous phase. The gels demonstrated thermoreversibility with robust gel network. At temperatures near the skin surface temperature, the gels softened considerably and moreover, it facilitated the drug to accumulate in dermis, thus making an ideal delivery vehicle of cyclosporine topically that can be used in treatment of psoriasis. Thus amphiphilic gels were demonstrated as the ideal vehicle for topical use of cyclosporine.     

Crystal forms of atorvastatin

The objective of this work was to investigate the existence of new polymorphs and pseudopolymorphs of atorvastatin and the transformation of crystal forms. Three crystal forms of atorvastatin have been isolated by recrystallization and characterized by powder X-ray diffractometry (PXRD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TG). The PXRD and DSC patterns of the three crystal forms were different respectively and it was confirmed that Form 3 is a new crystal form. After storage of 2 years at room temperature, this new crystal form was not transformed and it was shown to have a good physical stability.     

Understanding the dehydration of levofloxacin hemihydrate

Levofloxacin is a broad-spectrum antibiotic that exists as a hemihydrate under ambient conditions. In addition to the hemihydrate, there are three known crystalline anhydrate forms, denoted as α, β, and γ. In this study, differential scanning calorimetry (DSC), thermogravimetric analysis, Raman spectroscopy, single-crystal and powder X-ray diffraction, and solid-state NMR spectroscopy were used to investigate the transitions that occurred upon dehydration to the anhydrate as well as additional transitions that occurred to the anhydrous material upon heating/cooling. An enantiotropic conversion was observed in the DSC around 54°C corresponding to the conversion of the γ form to a new form, denoted as the δ form. Raman spectroscopy, powder X-ray diffraction, and solid-state NMR spectroscopy confirmed that a new crystalline form was being produced.     

Solid state characterization of an neuromuscular blocking agent--GW280430A

GW280430A is an ultrashort-acting neuromuscular blocking agent and is targeted for muscle relaxation as part of the intubation surgical procedure. The objective of this work was to perform solid state characterization on GW280430A and to evaluate the relationship between water content and glass transition temperature (Tg). GW280430A was characterized by differential scanning calorimetry, thermogravimetric analysis, powder X-ray diffraction (PXRD), microscopy and moisture sorption. The effect of water content on the Tg of GW280430A was evaluated by equilibrating the material over saturated salt solutions at a range of relative humidities (6.4-72.6%) and determining the Tg by DSC using hermetically sealed aluminum pans. GW280430A undergoes dehydration at 40 degrees C, glass transition at 130 degrees C and decomposition at 190 degrees C by differential scanning calorimetry. By PXRD and moisture sorption, GW280430A is an amorphous material and deliquesces at about 70% RH at room temperature. Water acts as a potent plasticizer for GW280430A and the Tg decreases significantly as the water content increases. No measurable decomposition of GW280430A was observed after 4 weeks at 40 degrees C/75% RH.     

头孢唑林钠结晶热力学

采用差热分析法测定头孢唑林钠的分解温度和分解热；采用激光法测定头孢唑林钠在不同配比的水-乙醇、水-丙酮、水-异丙醇混合溶剂中的溶解度数据。采用指数模型对溶解度数据进行关联；最后测定头孢唑林钠在水及水与异丙醇混合溶剂中的冷却结晶介稳区数据，为头孢唑林钠的工业生产提供热力学依据。     

Diclofenac solubility: independent determination of the intrinsic solubility of three crystal forms

The solubility in water of diclofenac ({2-[(2,6-dichlorophenyl)amino]phenyl}acetic acid), a potent nonsteroidal anti-inflammatory drug, has been investigated. The various solid forms have been characterized by thermogravimetric analysis, differential scanning calorimetry, and X-ray diffraction. The commercially available form of diclofenac is the anhydrous sodium salt. This was recrystallized from ethanol and precipitated as a hydrate containing four diclofenac anions, four sodium cations, and nineteen water molecules per unit cell. This crystal structure is similar to but different from an earlier report of the structure. Crystals of the acid form of diclofenac were anhydrous and corresponded to an earlier crystal structure. Separate solubility measurements on all three of these solid forms of diclofenac gave consistent results for the intrinsic solubility. The aqueous solubility values reported in the literature for diclofenac are spread over a large range, with a factor of 100 separating the largest and the smallest. Our value is at the smaller end of this range. It is the only one supported by three independent procedures and rigorous characterization of the solid forms. The experimental conditions were precisely controlled.     

Structural Characterization and Pharmaceutical Properties of Three Novel Cocrystals of Ethenzamide With Aliphatic Dicarboxylic Acids

Ethenzamide (ET) was screened in cocrystallization experiments with pharmaceutically acceptable coformer molecules to discover materials of improved physicochemical properties, that is, higher solubility and better stability. Three novel cocrystals of ET with glutaric, malonic, and maleic acids were obtained by neat grinding and slow evaporation from solution. The purpose of the study was to notice the changes in the geometry and interactions of ET molecule in crystalline phase introduced by different acid and relate them to physicochemical properties of pure ET. Therefore, the crystal structure of the cocrystals was determined by single crystal X-ray diffraction analysis. The powder samples were characterized by differential scanning calorimetry, Fourier-transform infrared spectroscopy, and ¹³C and ¹⁵N solid-state nuclear magnetic resonance spectroscopy. Spectroscopic studies were supported by gauge including projector augmented wave calculations of chemical shielding constants. The high stability of cocrystals during direct compression was proved. The solubility in simulated gastric fluids for studied cocrystals appeared to be approximately 1.6 times-fold higher than ET. The dissolution rates of all ET cocrystals were not faster than the pure drug, but after 240 min, more drugs were released.