Papers and patents that deal with polymorphism (crystal systems for which a substance can exist in structures characterized by different unit cells, but where each of the forms has exactly the same elemental composition) and solvatomorphism (systems where the crystal structures of the substance are defined by different unit cells, but where these unit cells differ in their elemental composition through the inclusion of one or molecules of solvent) have been summarized in an annual review. The works cited in this review were published during 2007, and were drawn from the major physical, crystallographic, and pharmaceutical journals. The review is divided into sections that cover articles of general interest, computational and theoretical studies, preparative and isolation methods, structural characterization and properties of polymorphic and solvatomorphic systems, studies of phase transformations, effects associated with secondary processing, and United States patents issued during 2007.

Pantoprazole is a proton pump inhibitor prodrug used in the treatment of gastric ulcers and gastroesophageal disease. Pantoprazole must be absorbed in the gastrointestinal tract and because it is unstable under acidic conditions, enteric delivery systems are required. The purpose of this study was to prepare pantoprazole-loaded microspheres by emulsion-solvent evaporation technique using two different types of enteric-coating polymers: Eudragit S 100 and hydroxypropyl methylcellulose phtalate. The microspheres have been characterized in terms of their morphology, encapsulation efficiency, and ability of stabilizing pantoprazole in acidic media. Pantoprazole determinations were carried out using a validated spectrophotometric method for the analysis of drug in dissolution media. All microspheres, except F2 formulation, were successfully obtained. The in vitro assay showed that especially F1 and F4 microspheres were more effective in protecting the drug than F3 microspheres in acidic media.

Four crystal modifications of acyclovir were isolated by recrystallization and characterized by powder X-ray diffractometry, differential scanning calorimetry, and thermogravimetric analysis. It was confirmed that Form 3 is a hydrate and Form 4 is an acetic acid solvate. The dissolution patterns of three crystal forms of acyclovir were studied in water at 37 +/- 0.5 degrees C, 90 rpm for 120 minutes. The amount dissolved at 120 minutes was highest for Form 1, followed by Form 2 and Form 3. After storage of 25 hours at 0% RH (silica gel, 20 degrees C) Form 3 was transformed to Form 2.

Microparticles of poly(epsilon-caprolactone) and of its blend with Eudragit(R) S100 were prepared by emulsion/solvent evaporation technique to provide controlled release and gastro-resistance for an acid labile drug. This drug was sodium pantoprazole, a proton pump inhibitor. Both formulations were successfully prepared, but only the microparticles prepared with the blend were capable of stabilizing the drug in the acid medium. Furthermore, this formulation showed in vivo protection of stomachs against ulceration caused by ethanol in rats. These microparticles were tabletted, and the tablets demonstrated slower drug release and higher acid protection than the microparticles before tabletting.

Papers and patents that deal with polymorphism (crystal systems for which a substance can exist in structures characterized by different unit cells, but where each of the forms consists of exactly the same elemental composition) and solvatomorphism (systems where the crystal structures of the substance are defined by different unit cells, but where these unit cells differ in their elemental composition through the inclusion of one or molecules of solvent) have been summarized in an annual review. The works cited in this review were published during 2005, and were drawn primarily from the major physical, crystallographic, and pharmaceutical journals. The review is divided into sections that cover articles of general interest, computational and theoretical studies, preparative and isolation methods, structural characterization and properties of polymorphic and solvatomorphic systems, studies of phase transformations, effects associated with secondary processing, and United States patents issued during 2005.

Pantoprazole is an important drug in the treatment of acid-related disorders. This work concerns the preparation and characterization of gastro-resistant pantoprazole-loaded microparticles prepared using an O/O emulsification/solvent evaporation technique. The in vivo activity of the pantoprazole-loaded Eudragit((R)) S100 microparticles was carried out in rats. Furthermore, tablets containing the microparticles were also investigated. Microparticles presented spherical and smooth morphologies (SEM) and they remained intact in the inner surface of tablets. DSC and IR analyses showed that pantoprazole was physically and molecularly dispersed in the polymer. In vivo anti-ulcer evaluation showed that the microparticles were able to protect rat stomachs against ulcer formation, while the drug aqueous solution did not present activity. Drug dissolution profiles from tablets demonstrated slower release than untabletted microparticles. Weibull equation was the best model for describing the drug release profiles from microparticles and tablets. As regards the acid protection, tablets showed a satisfactory drug protection in acid medium (61.05+/-8.09% after 30min).

The present study showed, that the crystal structures of R-isomer and the polymorphic form 1 of clopidrogrel hydrogensulphate S-isomer are very similar.

A delivery system which provides bimodal pH dependent release of poorly water soluble carvedilol in gastric and intestinal environment was designed. Preparation of solid dispersion with porous silica ensured a significantly higher dissolution rate of carvedilol in acidic and alkaline media in comparison to pure drug, while granulation of that solid dispersion with enteric polymer dispersion resulted in diminished immediate release in acidic media and fast release of the remaining drug in alkaline media. The ratio in quantities of first vs. second release was controlled with amount of enteric polymer dispersion used for granulation process. Desired 25 mg release of carvedilol at pH values 1.2 and 6.8 was achieved when 1.80 g of polymer per 1.0 g of solid dispersion (drug to silica ratio= 0.25 g : 2.0 g) was used.

When ionic polymers (polyelectrolytes) are used as excipients in pharmaceutical formulations, the properties of oppositely charged drugs may be strongly affected by the charge-charge interactions or complex formation. Usually these effects are considered as a negative event resulting in a drug-excipient incompatibility. Sometimes ionic interactions are preferred to prolong drug release from dosage forms in a controllable manner. Ionic interactions of carrageenans with doxazosin mesylate were confirmed by differential scanning calorimetry (DSC). Evident peak shifts and shape changes of assumed desulfation peak of carrageenans in concordance with disappearance of melting peak of doxazosin mesylate (DM) in DSC curves were obtained. The range of thermal effects is depended on the ratio of doxazosin mesylate and carrageenans. The higher the ratio of DM compared to CARRs the more evident are the interactions.

The effects of process conditions and binder content on the process yield and pellet characteristics of two formulations prepared by melt pelletization in a laboratory-type high shear mixer were investigated. The formulations were prepared using Gelucire 50/13 and Lutrol F68 as meltable binders. The factors under investigation were impeller speed, mixing time, mixer load, binder concentration, and their reciprocal interactions. Analysis of variance (ANOVA) was used in order to study the significance of above mentioned process variables on the useful yield. Twenty-seven experiments were required for the response surface methodology based on Box-Behnken experimental design (24 combinations with three replications of the centre point) for each formulation. The control over the process and the quality of the resulting pellets were found to depend on the rheological properties of the binders used. In the case of a low viscosity binder (Gelucire 50/13), the process was easily controllable whereas in the case of a high viscosity binder (Lutrol F68), the process was more difficult to control. The useful yield of the formulation in the case of the low viscosity binder was found to be mostly influenced by the concentration of the binder. On the other hand, different binder concentrations did not affect the useful yield of the formulation prepared by use of the high viscosity binder. In the latter case, mixing time was identified as the variable that mostly influenced the pelletization process. Finally response surface methodology was applied to find the optimum values of the process variables.

The aim of our research was to apply experimental design methodology in the development and optimization of drug release methods. Diclofenac sodium (2-[(2,6-dichlorophenyl)amino]benzeneacetic acid monosodium salt) was selected as a model drug and Naklofen retard prolonged release tablets, containing 100 mg of diclofenac sodium, were chosen as a model prolonged release system. On the basis of previous results, a three-level three-factorial Box-Behnken experimental design was used to characterize and optimize three physicochemical parameters, i.e. rotation speeds of the stirring elements, pH, and ionic strengths of the dissolution medium, affecting the release of diclofenac sodium from the tablets. The chosen dependent variables (responses) were a cumulative percentage of dissolved diclofenac sodium in 2, 6, 12 and 24 h. For estimation of coefficients in the approximating polynomial function, the least square regression method was applied. Afterwards, the information about the model reliability was verified by using the analysis of variance (ANOVA). The estimation of model factors' significance was performed by Student's t-test. For investigation of the shape of the predicted response surfaces and for model optimization, the canonical analysis was applied. Our study proved that experimental design methodology could efficiently be applied for characterization and optimization of analytical parameters affecting drug release and that it is an economical way of obtaining the maximum amount of information in a short period of time and with the fewest number of experiments.

The aim of this research was to develop and optimize the drug release determination of iron from iron prolonged release tablets. First, solubility characteristics of ferrous sulfate in different aqueous media with a pH in the range of 1 to 8 were studied. According to the results obtained different physicochemical conditions that influence drug release of iron from iron prolonged release tablets were checked. Various aqueous media with a pH in the range of 1 to 7.4, different volumes of dissolution media, various rotation speeds of stirring elements, different dissolution apparatus (apparatus 1/basket apparatus and apparatus 2/paddle apparatus according to USP/Ph. Eur.) were verified. For evaluation of dissolved iron two different methods were checked: atomic absorption spectrometry and redox titration. Redox titration was proved to be a reproducible, discriminatory, selective and cost effective method for evaluation of dissolved iron from iron prolonged release tablets and can be applied in the quality control of solid dosage forms containing iron compounds.

The objective of the present study was to evaluate three formulation parameters for the application of polymethacrylic films from aqueous dispersions in order to obtain multiparticulate sustained release of diclofenac sodium. Film coating of pellet cores was performed in a laboratory fluid bed apparatus. The chosen independent variables, i.e. the concentration of plasticizer (triethyl citrate), methacrylate polymers ratio (Eudragit RS:Eudragit RL) and the quantity of coating dispersion were optimised with a three-factor, three-level Box-Behnken design. The chosen dependent variables were cumulative percentage values of diclofenac dissolved in 3, 4 and 6 h. Based on the experimental design, different diclofenac release profiles were obtained. Response surface plots were used to relate the dependent and the independent variables. The optimisation procedure generated an optimum of 40% release in 3 h. The levels of plasticizer concentration, quantity of coating dispersion and polymer to polymer ratio (Eudragit RS:Eudragit RL) were 25% w/w, 400 g and 3/1, respectively. The optimised formulation prepared according to computer-determined levels provided a release profile, which was close to the predicted values. We also studied thermal and surface characteristics of the polymethacrylic films to understand the influence of plasticizer concentration on the drug release from the pellets.

Piroxicam polymorphism was extensively studied in the past. The objective of the present work was to evaluate polymorphism of piroxicam once again and to characterize the obtained crystal forms. Three polymorphic forms and one monohydrate form were obtained by crystallization from saturated solutions in various solvents. Polarity of solvents and crystallization rate defined by temperature of crystallization were found to be critical parameters in determining the polymorphic form. A new polymorphic form designated as form III was obtained by forced crystallization using dry ice. Only form I with the highest melting point was found to be stable under mechanical and thermal stress. Differences in IR spectra were attributed mainly to the differences in number and positions of H-bonds in the piroxicam crystal forms. Slow crystallization of piroxicam from absolute ethanol solution resulted in a mixture of form II and monohydrate. Crystal structure analysis proved that form II represents form alpha(2) already proposed in the literature. Differences in dissolution rates among crystal forms of piroxicam were attributed to differences in their wettability, where highest wettability was obtained for monohydrate and the lowest for form III.

Enalaprilat is a typical angiotensin-converting enzyme inhibitor and is very poorly absorbed from the gastrointestinal tract. The aim of this study was to design and characterize poly-(lactide-co-glycolide)(PLGA) and polymethylmethacrylate (PMMA) nanoparticles containing enalaprilat and to evaluate the potential of these colloidal carriers for the transport of drugs through the intestinal mucosa. Nanoparticle dispersions were prepared by the emulsification-diffusion method and characterized according to particle size, zeta potential, entrapment efficiency and physical stability. Effective permeabilities through rat jejunum of enalaprilat in solution and in enalaprilat-loaded nanoparticles were compared using side-by-side diffusion chambers. The solubility of enalaprilat is very low in many acceptable organic solvents, but in benzyl alcohol is sufficient to enable the production of nanoparticles by the emulsification-diffusion process. The diameters of drug-loaded PMMA and PLGA nanoparticles were 297 and 204 nm, respectively. The concentration of the stabilizer polyvinyl alcohol (PVA) in dispersion has an influence on particle size but not on drug entrapment. The type of polymer has a decisive influence on drug content--7 and 13% for PMMA and PLGA nanoparticles, respectively. In vitro release studies show a biphasic release of enalaprilat from nanoparticle dispersions-fast in the first step and very slow in the second. The apparent permeability coefficient across rat jejunum of enalaprilat entrapped in PLGA nanoparticles is not significantly improved compared with enalaprilat in solution.

The purpose of this research is to apply near infrared spectrometry (NIR) with chemoinformetrics to predict the change of crystalline properties of indomethacin (IMC) amorphous under various levels of relative humidity storage conditions. Stability test for amorphous and meta-stable polymorphic forms was performed in humidity controlled the modified 96-well quartz plates containing various kinds of saturated salt solutions (0-100% of relative humidity (RH)) by NIR spectroscopy. Amorphous form was obtained melt product to pour into liquid nitrogen and after then ground. Samples were stored at 25°C in the 6-well plates at various levels of RH. The spectra of the powder samples were measured by the reflectance FT-NIR spectrometer. The second derivative spectra of form α showed specific absorption peaks at 4980, 6036, 7296 and 8616 cm-1 and that of form γ showed those at 5020, 5028, 7344, 7428 and 8436 cm-1. After storage at less than 50% RH, the peak intensities at 5020, 5028, 7344, 7428 and 8436 cm-1 of the amorphous solid increased with increasing of storage time. However, the peak intensity at 4980, 6036 and 7296 cm-1 increased at more than 50% RH Please check and confirm the edit. The results suggested that at lower humidity, the IMC amorphous solid transformed into form γ, but it transformed into form α at more than high humidity. It is possible that crystalline stability of the pharmaceutical preparations could be predicted by using humidity controlled 96-well plates and reflectance NIR-chemoinformetric methods.

In this study, the potential of perfusion calorimetry in the characterization of solvates forming isomorphic desolvates was investigated. Perfusion calorimetry was used to expose different hydrates forming isomorphic desolvates (emodepside hydrates II-IV, erythromycin A dihydrate and spirapril hydrochloride monohydrate) to stepwise increasing relative vapour pressures (RVP) of water and methanol, respectively, while measuring thermal activity. Furthermore, the suitability of perfusion calorimetry to distinguish the transformation of a desolvate into an isomorphic solvate from the adsorption of solvent molecules to crystal surfaces as well as from solvate formation that is accompanied by structural rearrangement was investigated. Changes in the samples were confirmed using FT-Raman and FT-IR spectroscopy. Perfusion calorimetry indicates the transformation of a desolvate into an isomorphic solvate by a substantial exothermic, peak-shaped heat flow curve at low RVP which reflects the rapid incorporation of solvent molecules by the desolvate to fill the structural voids in the lattice. In contrast, adsorption of solvent molecules to crystal surfaces is associated with distinctly smaller heat changes whereas solvate formation accompanied by structural changes is characterized by an elongated heat flow. Hence, perfusion calorimetry is a valuable tool in the characterization of solvates forming isomorphic desolvates which represents a new field of application for the method.

The effects of spray-drying process and acidic solvent system on physicochemical properties of chitosan salts were investigated. Chitosan used in spray dryings was obtained by deacetylation of chitin from lobster (Panulirus argus) origin. The chitosan acid salts were prepared in a laboratory-scale spray drier, and organic acetic acid, lactic acid, and citric acid were used as solvents in the process. The physicochemical properties of chitosan salts were investigated by means of solid-state CP-MAS (13)C nuclear magnetic resonance (NMR), X-ray powder diffraction (XRPD), differential scanning calorimetry, and Fourier transform infrared spectrometry (FTIR) and near-infrared spectroscopy. The morphology of spray-dried chitosan acid salts showed tendency toward higher sphericity when higher temperatures in a spray-drying process were applied. Analysis by XRPD indicated that all chitosan acid salts studied were amorphous solids. Solid-state (13)C NMR spectra revealed the evidence of the partial conversion of chitosan acetate to chitin and also conversion to acetyl amide form which appears to be dependent on the spray-drying process. The FTIR spectra suggested that the organic acids applied in spray drying may interact with chitosan at the position of amino groups to form chitosan salts. With all three chitosan acid salts, the FTIR bands at 1,597 and 1,615 cm(-1) were diminished suggesting that -NH groups are protonated. The FTIR spectra of all chitosan acid salts exhibited ammonium and carboxylate bands at 1,630 and 1,556 cm(-1), respectively. In conclusion, spray drying is a potential method of preparing acid salts from chitosan obtained by deacetylation of chitin from lobster (P. argus) origin.

The aim of this work was to evaluate a crystalline nanosuspension of an investigational anticancer compound, SN 30191. Solid forms of SN 30191 were prepared and characterized by thermal analysis, infrared spectroscopy, ¹³C CP/MAS SSNMR spectroscopy, SEM and powder XRD. Wet milling was performed using a high pressure homogenizer and process induced transformations were studied as a function of time and pressure using infrared spectroscopy. Dose-toxicity and pharmacokinetics (PK) of the nanocrystal formulation were evaluated in mice after intravenous administration. SN 30191 was found to exist in two polymorphic forms (I and II) and a hydrate with an equilibrium solubility < 0.1 μg/ml (pH 1.3-11.0, 37 °C). Wet milling resulted in solid state transformation as a function of pressure. Form II was found to transform into form I at intermediate pressures. A further increase in pressure resulted in formation of a hydrate. The final nanosuspension consisted of SN 30191 as a hydrate. The dose-toxicity studies revealed higher tolerance (~4 times) for the nanosuspension (10 mg/kg) when compared with a solution formulation (2.5 mg/kg). Compared with solution formulation, the nanosuspension allowed the delivery of a higher dose and rendered possible the performance of PK and tissue distribution studies in animals.

TRK-720 has been under development as a dry powder inhaler (DPI) for treating bronchial asthma. DPI is a drug formulation of an active pharmaceutical ingredient (API) supported by carrier particles. On inhalation, the API particles dissociate from the carriers through physical stimulation and reach the lung through the humid upper airways, therefore, the API has to remain physically and chemically stable despite contact with carriers and low relative humidity. Also it should be pulverized into an appropriate size (1-10 microm) for reaching the target region. To fulfill these requirements, API in crystal form is needed. Polymorphic screening using 42 solvents produced 9 solvates but not the target hydrate or ansolvate crystal. When the solvent was removed from each solvate, only methanolate could reproducibly be converted into hydrate by water vapor substitution. As the hydrate satisfied the above requirements for DPI, it was selected as a solid form for development. Also, the results of single crystal X-ray structural analyses and calculations of crystal packing energies, for five of the solvates, indicated that only the methanolate can be converted into the hydrate through solvent substitution.

1,3-dipropyl-8-cyclopentylxanthine (CPX) has been shown to stimulate in vitro CFTR activity in F508 cells. Data from a phase I study demonstrated erratic bioavailability and no measurable clinical response to oral CPX. One cause for its poor bioavailability may have been dissolution rate limited absorption, but there is little published physicochemical data on which to base an analysis. The objective of this study was to determine the solubility and solid-state characteristics of CPX. CPX is a weak acid with pKa of 9.83 and water solubility at pH 7.0 of 15.6 microM. Both laureth-23 and poloxamer 407 increased the apparent water solubility linearly with increasing concentrations. CPX exists in two crystal forms, one of which (form II) has been solved. Form II is a triclinic crystal with space group P1 and calculated density of 1.278 g/cm(3). X-ray powder diffraction and differential scanning calorimetry studies (DSC) indicated that CPX crystals prepared at room temperature were mixtures of forms I and II. DSC results indicated a melting point of approximately 195 degrees C for form I and 198 degrees C for form II. Thermogravimetric analysis indicated no solvent loss upon heating. Dynamic water vapor sorption data indicated no significant water uptake by CPX up to 90% RH. Analysis of the data indicates that CPX may not be amenable to traditional formulation approaches for oral delivery.

Five new polymorphs and one hydrated form of 2-thiobarbituric acid have been isolated and characterised by solid-state methods. In both the crystalline form II and in the hydrate form, the 2-thiobarbituric molecules are present in the enol form, whereas only the keto isomer is present in crystalline forms I (reported in 1967 by Calas and Martinex), III, V and VI. In form IV, on the other hand, a 50:50 ordered mixture of enol/keto molecules is present. All new forms have been characterised by single-crystal X-ray diffraction, 1D and 2D ((1)H,(13)C, and (15)N) solid-state NMR spectroscopy, Raman spectroscopy and X-ray powder diffraction at variable temperature. It has been possible to induce keto-enol conversion between the forms by mechanical methods. The role of hydrogen-bond interactions in determining the relative stability of the polymorphs and as a driving force in the conversions has been ascertained. To the best of the authors' knowledge, the 2-thiobarbituric family of crystal forms represents the richest collection of examples of tautomeric polymorphism so far reported in the literature.

Polymorph screening of Compound A, an investigational drug, revealed two anhydrous polymorphs (Forms I and II) and two monohydrates (Forms III and IV) of this pharmaceutical solid. The physiochemical properties of the four forms were characterized by thermal analysis, hot-stage microscopy, equilibrium solubility and intrinsic dissolution rate measurements, and X-ray powder diffraction. Inter-conversion relationship of the four forms was fully elucidated. Thermodynamic stability relationship was inferred from melting data for Form I and Form II and evaluated by van't Hoff plot for Form III and Form IV. Form I and Form III were found to be the more stable anhydrous and hydrate form, respectively. Anhydrous Form I was selected for further pharmaceutical development.

The stabilizing ability of the excipient on pharmaceutically relevant proteins for potential therapeutic use is an extensive area of research but the effect the protein has on the excipient is rarely reported. The influence of two model proteins on the polymorphic behaviour of mannitol during spray drying was therefore investigated. Spray dried mannitol/protein blends were characterised structurally using X-ray powder diffraction (XRPD) and Fourier transform Raman spectroscopy (FT-Raman) and thermally by differential scanning calorimetry (DSC) and also thermogravimetric analysis (TGA). To assess the long term storage stability, samples were subjected to conditions of elevated temperature and relative humidity (RH). Structural and thermal analysis of the samples showed that upon spray drying mannitol could be completely amorphous or crystalline dependent on the protein co-spray dried. Upon storage at elevated temperature and RH different polymorphic forms of mannitol (beta and delta) were evident again dependent on the protein co-spray dried. Under the conditions employed there was a polymorph directing effect on mannitol dependent on the protein with which it was co-spray dried with co-solute effects on relative water levels being indicated as a major factor in directing the polymorph.

To develop a novel tacrolimus-loaded solid dispersion with improved solubility, various solid dispersions were prepared with various ratios of water, sodium lauryl sulfate, citric acid and carboxylmethylcellulose-Na using spray drying technique. The physicochemical properties of solid dispersions were investigated using scanning electron microscopy, differential scanning calorimetery and powder X-ray diffraction. Furthermore, their solubility and dissolution were evaluated compared to drug powder. The solid dispersion at the tacrolimus/CMC-Na/sodium lauryl sulfate/citric acid ratio of 3/24/3/0.2 significantly improved the drug solubility and dissolution compared to powder. The scanning electron microscopy result suggested that carriers might be attached to the surface of drug in this solid dispersion. Unlike traditional solid dispersion systems, the crystal form of drug in this solid dispersion could not be converted to amorphous form, which was confirmed by the analysis of DSC and powder X-ray diffraction. Thus, the solid dispersion system with water, sodium lauryl sulfate, citric acid and CMC-Na should be a potential candidate for delivering a poorly water-soluble tacrolimus with enhanced solubility and no convertible crystalline.