Hyphenated spectroscopy as a polymorph screening tool

Polymorph screening of a model compound (nitrofurantoin) was performed. Nitrofurantoin was crystallized from acetone-water mixtures with varying process parameters. Two anhydrate forms (alpha and beta) and one monohydrate form (II) were crystallized in the polymorph screen. The solid forms were analyzed with three complementary spectroscopic techniques: near-infrared (NIR) spectroscopy, Raman spectroscopy and terahertz pulsed spectroscopy (TPS), and the results of the solid phase analysis were verified with X-ray powder diffraction (XRPD). NIR and Raman spectroscopy were coupled to achieve a rapid and comprehensive method of solid phase analysis. The hyphenated NIR/Raman spectroscopic data were analyzed with a multivariate method, principal component analysis (PCA). The combination was found effective in screening solid forms due to the complementary characteristics of the methods. NIR spectroscopy is powerful in differentiating between anhydrate and hydrate forms and intermolecular features, whereas Raman spectroscopy is sensitive to intramolecular alterations in the molecular backbone.     

Investigation of excipient and processing on solid phase transformation and dissolution of ciprofloxacin

Ciprofloxacin, a very slightly soluble antibiotics, is known to exist as both anhydrous and hydrous forms. This study was carried out to investigate the solid phase transformation of ciprofloxacin during conventional formulation processing that impacts the performance of solid dosage forms. In addition, alternative processing and formulation options were also evaluated to circumvent phase transformation. Anhydrate and hydrate of ciprofloxacin were characterized using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), powder X-ray diffraction (PXRD) and powder dissolution. As expected, the anhydrate exhibited significantly higher dissolution rate than the hydrate. However, it rapidly converted to the hydrate upon exposure to aqueous medium. Interestingly, premixing the anhydrate with HPMC in the presence of water or ethanol was found to inhibit the processing-induced phase transition. Further studies demonstrated that wet granulation could be an option for preparing tablets with high loading of ciprofloxacin anhydrate through proper selection of excipients and control of processing conditions. Dissolution study of ciprofloxacin in HPMC based extended release matrix tablets indicated different dissolution rates between tablets containing the anhydrate and hydrate, suggesting transformation to the hydrate was significantly inhibited by HPMC in the gel layer of the hydrated tablets.     

Influence of the Solid Form of Siramesine Hydrochloride on its Behavior in Aqueous Environments

Purpose  To study the influence of solid form on the behavior of the salt siramesine hydrochloride in aqueous environments. Methods  The solubilities and dissolution rates of siramesine hydrochloride anhydrate and monohydrate were determined at pH 3.4 and 6.4, and precipitates were examined by X-ray powder diffraction. The mechanism of anhydrate–hydrate conversion was investigated by optical microscopy, and wet massing of the anhydrate was carried out using water and 60% (v/v) ethanol separately as granulation liquids. The wet masses were analyzed using Raman microscopy. Results  At pH 3.4 the anhydrate and monohydrate salts exhibited similar dissolution profiles. At pH 6.4 both the anhydrate and monohydrate salts formed supersaturated solutions of high apparent solubility. From the anhydrate solution, precipitation of the free base occurred, while the solution of the monohydrate salt remained in the supersaturated state. This resulted in a superior dissolution profile of the monohydrate salt. Microscopy and wet massing experiments showed that the anhydrate–hydrate conversion of siramesine hydrochloride was solution-mediated and dissolution-controlled. Conclusion  During development of a formulation based on the anhydrate salt, the risk of processing-induced transformation to the monohydrate form as well as precipitation of the free base should be considered.     

Physical characterization of erythromycin: anhydrate, monohydrate, and dihydrate crystalline solids

Hot-stage microscopy, thermoanalytical methods, and X-ray powder diffraction were used to demonstrate that crystalline erythromycin dihydrate converts to the crystalline anhydrate via a noncrystalline intermediate. X-ray powder diffraction, IR spectral, thermogravimetric, and differential thermal analyses were used to characterize the monohydrate material. The flow interrupt technique, a procedure recently developed to deal with low surface area samples, was employed successfully in obtaining isotherms and specific surface areas for the monohydrate and anhydrate. The relative dissolution rates of the various hydrates were determined in an aqueous solution (0.01 M phosphate buffer, pH 7.5) at 37 degrees. The results showed a significant difference in the dissolution rate of the dihydrate compared to the monohydrate and anhydrate.     

Structural and analytical characterization of three hydrates and an anhydrate form of risedronate

Four hydration states are reported for Risedronate monosodium. A single-crystal X-ray structure determination is provided as proof of assignment for the monohydrate, hemi-pentahydrate, and variable hydrate forms. The structure provided for the anhydrate form was determined through simulating annealing calculations and subsequent Reitveld refinement of a high-quality X-ray powder diffraction patterns Favorable comparisons of experimentally obtained X-ray powder patterns are made to those generated from the single crystal data. Characteristic infrared, Raman, and NMR spectra are provided and discussed for each form as are thermal analysis profiles. In addition, photomicrographs are provided for each of the forms isolated for this study. The hemi-pentahydrate is demonstrated to be the equilibrium form at room temperature and 37 degrees C, in the presence of water.     

Physical and structural comparison of oxyphenbutazone monohydrate and anhydrate

Two crystal forms of oxyphenbutazone (a monohydrate and an anhydrate) were prepared by recrystallization. The forms were characterized by means of differential scanning calorimetry, thermogravimetry, infrared spectrophotometry, X-ray powder diffraction patterns, thermomicroscopy, scanning electron microscopy, as well as powder and intrinsic dissolution rates. The crystal structure of the anhydrate has been elucidated and compared with that of the monohydrate.     

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.     

Effects of excipients on hydrate formation in wet masses containing theophylline

Transformations between solid phases in dosage forms can lead to instability in drug release. Thus, it is important to understand mechanisms and kinetics of phase transformations and factors that may influence them. During wet granulation theophylline shows pseudopolymorphic changes that may alter its dissolution rate. The aim of this study was to investigate whether excipients, such as alpha-lactose monohydrate or the highly water absorbing silicified microcrystalline cellulose (SMCC) can influence the hydrate formation of theophylline. In particular, the aim was to study if SMCC offers protection against the formation of theophylline monohydrate relative to alpha-lactose monohydrate in wet masses after an overnight equilibration and the stability of final granules during controlled storage. In addition, the aim was to study the use of spectroscopic methods to identify hydrate formation in the formulations containing excipients. Off-line evaluation of materials was performed using X-ray powder diffractometry, near infrared and Raman spectroscopy. alpha-Lactose monohydrate with minimal water absorbing potential was not able to prevent but enhanced hydrate formation of theophylline. Even though SMCC is able to take large amounts of water into its internal structure, it was able to inhibit the formation of theophylline monohydrate only at low moisture contents, not at the amounts of water needed to form granules. Both the spectroscopic methods used could identify the hydrate formation even though there were excipients in the formulation.     

Role of excipients in hydrate formation kinetics of theophylline in wet masses studied by near-infrared spectroscopy.

Hydrate formation is a phase transition, which can occur during wet granulation. This kind of processing-induced transformation (PIT) can influence the quality of a finished product. The aim of the study was to investigate the effect of excipients on the kinetics of hydrate formation in wet masses. Anhydrous theophylline was chosen as the hydrate-forming model drug compound and two excipients, silicified microcrystalline cellulose (SMCC) and alpha-lactose monohydrate, with different water absorbing properties, were used in formulation. An early stage of wet massing was studied with anhydrous theophylline and its 1:1 (w/w) mixtures with alpha-lactose monohydrate and SMCC with 0.1g/g of purified water. The changes in the state of water were monitored using near-infrared spectroscopy, and the conversion of the crystal structure was verified using X-ray powder diffraction (XRPD). SMCC decreased the hydrate formation rate by absorbing water, but did not inhibit it. The results suggest that alpha-lactose monohydrate slightly increased the hydrate formation rate in comparison with a mass comprising only anhydrous theophylline.     

Preparation and physicochemical properties of niclosamide anhydrate and two monohydrates

The intent of the study was to prepare and characterize three crystal forms of niclosamide namely the anhydrate and the two monohydrates and to investigate the moisture adsorption and desorption behavior of these crystal forms. The crystal forms were prepared by recrystallization and were characterized by differential scanning calorimetry, thermogravimetric analysis, isoperibol solution calorimetry, Karl Fischer titration, and X-ray powder diffractometry. Moisture adsorption by the anhydrate at increased relative humidities and two temperatures, 30 and 40 degrees C, was measured while the desorption from the monohydrates was determined at 45, 55, and 65 degrees C for monohydrate H(A) and 75, 90, and 100 degrees C for monohydrate H(B). Thermal analysis and solution calorimetry showed that monohydrate H(B) is more stable than monohydrate H(A) and solubility measurements showed the solubility of the crystal forms decreased in the order: anhydrate>monohydrate H(A)>monohydrate H(B). With an increase in temperature and relative humidity niclosamide anhydrate adsorbed moisture to form monohydrate H(A) by a random nucleation process. Dehydration of monohydrate H(A) at increased temperatures followed zero order kinetics and resulted in a change to the anhydrate. Monohydrate H(B) was transformed to the anhydrate at higher temperatures by a three-dimensional diffusion mechanism.     

Structural Characterisation and Dehydration Behaviour of Siramesine Hydrochloride

In this study the crystal structures of siramesine hydrochloride anhydrate α-form and siramesine hydrochloride monohydrate were determined, and this structural information was used to explain the physicochemical properties of the two solid forms. In the crystal structure of the monohydrate, each water molecule is hydrogen bonded to two chloride ions, and thus the water is relatively strongly bound in the crystal. No apparent channels for dehydration were observed in the monohydrate structure, which could allow transmission of structural information during dehydration. Instead destructive dehydration occurred, where the elimination of water from the monohydrate resulted in the formation of an oily phase, which subsequently recrystallised into one or more crystalline forms. Solubility and intrinsic dissolution rate of the anhydrate α-form and the monohydrate in aqueous media were investigated and both were found to be lower for the monohydrate compared to the anhydrate α-form. Finally, the interactions between water molecules and chloride ions in the monohydrate as well as changes in packing induced by water incorporation could be detected by spectroscopic techniques. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:3596–3607, 2009     

In vitro controlled release of antihypertensive drugs intercalated into unmodified SBA-15 and MgO modified SBA-15 matrices

The aim of the present study was two-fold: (1) to investigate the effect of pH and presence of surfactant sodium lauryl sulphate (SLS) on the solubility and dissolution rate of two solid-state forms of piroxicam (PRX), anhydrate (PRXAH) and monohydrate (PRXMH), and (2) to quantitatively assess the solid-phase transformation of PRXAH to PRXMH in slurry with a special interest to the impact on the solubility and dissolution behavior of the drug. X-ray powder diffractometry (XRPD), Raman spectroscopy and scanning electron microscopy (SEM) were used for characterization of the solid-state forms. Phase transformation was monitored in slurry by means of in-line Raman spectroscopy, and the partial least squares (PLS) regression model was used for predicting the amount of PRXMH. The results showed that the solubility and dissolution rate of PRXAH were higher compared to PRXMH at different pHs. The pH and presence of SLS together affected the solubility and dissolution rate of different PRX forms. The lowest solubility values and dissolution rates for PRX forms were observed in distilled water (pH 5.6) at 37 °C. The changes in the dissolution rate could be explained by the hydrate formation during solubility testing. The rate of hydrate formation was also dependent on the pH of the dissolution medium.     

Influence of sample characteristics on quantification of carbamazepine hydrate formation by X-ray powder diffraction and Raman spectroscopy.

This study aimed to assess the suitability of two widely utilized solid state characterization techniques namely powder X-ray diffraction (XRPD) and Raman spectroscopy, in polymorph detection and quantification for carbamazepine anhydrate and dihydrate mixtures. The influences of particle size, particle morphology, mixing, and in particular, surface bias on quantitation were investigated. Binary mixtures of carbamazepine anhydrate (form III) and dihydrate were prepared and analyzed using both XRPD and Raman spectroscopy in combination with partial least squares analysis. It was found that in principle both XRPD and Raman spectroscopy could be used to build calibration models for quantitative analysis, and a satisfactory correlation between the two techniques could be achieved. However, Raman spectroscopy appeared to be a more reliable quantification method because problems such as different particle size, morphology, and special distribution of the two solid state forms of the drug seemed to have no significant influence on Raman scattering in this study. The robust nature of Raman analysis greatly facilitates the whole quantification process from the preparation of calibration models to the quantification of in situ CBZ-DH conversion.     

Solid-state characterization of fluconazole

Two polymorphs and three solvates of fluconazole were isolated and characterized by x-ray powder diffractometry, IR spectroscopy, differential scanning calorimetry (DSC), thermogravimetry, and their dissolution rates. The different forms were prepared by crystallization of the original powder in different solvents at different cooling rates. X-ray diffraction patterns of the five solid modifications exhibited substantial differences in both the intensity and position of the peaks. FTIR spectra of the five different solid-state modifications also exhibited differences in the peaks' positions and intensities. DSC thermogram of anhydrate form I showed a single melting point at 139.2 degrees C. Anhydrate form II showed two endothermic peaks at 136.5 and 139.2 degrees C and one exothermic peak in between. The DSC thermogram of acetone 1/4 solvate exhibited two endothermic peaks at 75.5 and 139.2 degrees C. Benzene 1/7 solvate exhibited two endothermic peaks at 131.5 and 138.8 degrees C. Hydrate E exhibited two endothermic peaks at 102.7 and 139.2 degrees C. The DSC thermogram of anhydrate form II showed that this form is sensitive to the application of a mechanical force. The solubility study showed that anhydrate form II and acetone 1/4 solvate have higher solubilities than anhydrate form I while benzene 1/7 solvate and monohydrate have lower solubilities than anhydrate form I. The intrinsic dissolution study confirmed these results.     

Drug hydrate systems and dehydration processes studied by terahertz pulsed spectroscopy

Terahertz pulsed spectroscopy was used to distinguish between different hydrate systems. In the example of four pharmaceutical materials lactose, carbamazepine, piroxicam and theophylline it was demonstrated that all different hydrate and anhydrate forms exhibit distinct spectra in the far infrared. Furthermore the dehydration of theophylline monohydrate was characterised in situ. Here, a phase transition from the monohydrate to the anhydrous form was observed, followed by evaporation of the hydrate water in a second step. The rotational spectrum of water vapour is very characteristic in the far infrared and can easily be discerned from the terahertz spectrum of the solid state form.     

Effect of Environmental Humidity on the Transformation Pathway of Nitrofurantoin Modifications During Grinding and the Physicochemical Properties of Ground Products

Abstract— The effect of humidity on the physicochemical properties of nitrofurantoin anhydrate and monohydrate during grinding in a humidity-controlled system was investigated using X-ray diffraction analysis, IR spectroscopy, thermal analysis and scanning electron microscopy. Anhydrate and monohydrate were transformed into a noncrystalline solid and a stable monohydrate, respectively, during grinding in a closed system. During grinding in an open system, in which the humidity level of the air was controlled (5, 50 and 75% r.h.), the anhydrate absorbed moisture from the supplied air and water content was increased at 75% r.h.; thereafter the compound was transformed into monohydrate II. The anhydrate did not absorb at 5 or 50% r.h. and was transformed into a noncrystalline solid. Monohydrate I desorbed crystal water during grinding at 5% r.h. and was transformed into a noncrystalline solid. However, monohydrate I was transformed into monohydrate II at 50 and 75% r.h. without desorption of crystal water. These results suggest that the solid-state transformation of nitrofurantoin during grinding depends upon the environmental humidity.     

X-ray crystallographic characterization of nilvadipine monohydrate and its phase transition behavior.

Crystals of nilvadipine monohydrate were obtained from aqueous acetonitrile solution and characterized by powder and single crystal X-ray crystallography and thermal analysis. Water molecules of crystallization exist in nilvadipine monohydrate crystals in a molar ratio of 1:1 (drug-to-water) and were fixed by three hydrogen bonds with two carbonyl groups of the methyl and isopropyl esters, respectively, and one imino group of neighboring nilvadipine molecules. The conformation of the methyl and isopropyl esters in the monohydrate crystal was the reversal of that in the anhydrate crystal due to the presence of hydrogen bonds with water in the former crystal. The monohydrate crystal was slowly converted to the dehydrate at low humidity, and the latter rapidly converted to the former at high humidity. Powder X-ray diffraction studies indicated that the dehydrate retains the original structure of the monohydrate, i.e., a layer structure stacked on the ac plane perpendicular to the b-axis The solubility of the monohydrate in water was lower than that of the dehydrate and anhydrate forms, although the initial dissolution rate of the monohydrate was faster than that of the anhydrate. The present results indicated that the conformation of 1, 4-dihydropyridine-type calcium channel antagonists such as nilvadipine is easily changed by hydrogen bonds with water molecules of crystallization, and the water molecules are mobile through the void spaces formed between the layers in crystals.     

Process‐Induced Phase Transformation of Berberine Chloride Hydrates

Berberine is a natural quaternary ammonium alkaloid used clinically in the chloride salt form for the treatment of diarrhea in many Asian countries. Although the hydrate formation of berberine chloride (BCl) is well documented, the associated mechanism and implications in pharmaceutical formulation have not been studied in detail. In this study, pure BCl dihydrate and BCl tetrahydrate were recrystallized from water and their phase transformation behaviors under defined conditions were investigated. Additionally, pharmacopoeial grade BCl material consisting predominantly of the dihydrate form was examined for potential phase changes when being subjected to a conventional wet granulation procedure for tablet production. Results from solubility measurements, thermal analysis, variable temperature‐powder X‐ray diffraction (VT‐PXRD), and variable temperature‐Fourier transform infrared spectroscopy (VT‐FTIR) confirmed the solid‐state interconversions between the tetrahydrate and dihydrate at 30–49°C and between the dihydrate and anhydrate at 70–87°C. Consistent with the observed phase changes of the two pure hydrates, wet massing of the pharmacopoeial grade BCl sample led to a thermodynamics‐driven transition to the tetrahydrate form at room temperature while subsequent tray drying at 50°C caused a reversion back to the dihydrate form. The rate and extent of such hydrate conversion depended largely on the water activity of the granulated powder matrix, which in turn was governed by the particular excipients employed. The present findings have important implications in the regulation of the hydrate forms of BCl in the finished products using specific excipients. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1942–1954, 2010     

Solid-state studies on the hemihydrate and the anhydrous forms of flunisolide

Flunisolide exists in at least two different anhydrous crystalline forms (I and II) and in a hemihydrate form with distinctly different physico-chemical properties. Modification II and the hemihydrate form are the commercial products. Form I was obtained by heating all other forms above 230 degrees C. The different crystalline forms of flunisolide were investigated by FTIR spectroscopy, X-ray powder diffractometry, differential scanning calorimetry (DSC), thermogravimetric analysis and thermomicroscopy both coupled with FTIR spectroscopy (TG-FTIR and FTIR thermomicroscopy). The three forms were easily differentiated by their IR spectra, X-ray powder diffraction patterns and thermal behaviour. Their stability was investigated under different experimental conditions to verify the tendency to solid solid transition and to study the existence range of the three forms. The relationship among the two anhydrous polymorphs and the hemihydrate form and their equilibrium solubilities in water at 20 degrees C were also investigated.     

Solid-state characterization and dissolution properties of Fluvastatin sodium salt hydrates

The present study reports the solid-state properties of Fluvastatin sodium salt crystallized from different solvents for comparison with crystalline forms of the commercially available raw material and United States Pharmacopeia (USP) reference standard. Fluvastatin (FLV) samples were characterized by several techniques; such as X-ray powder diffractometry, differential scanning calorimetry, thermogravimetry, liquid and solid-state nuclear magnetic resonance spectroscopy, diffuse reflectance infrared Fourier transform spectroscopy, and scanning electron microscopy. In addition, intrinsic dissolution rate (IDR) of samples was performed in order to study the influence of crystalline form and other factors on rate and extent of dissolution. Three different forms were found. The commercial raw material and Fluvastatin-Acetonitrile (ACN) were identified as “form I” hydrate, the USP reference standard as “form II” hydrate and an ethanol solvate which presented a mixture of phases. Form I, with water content of 4%, was identified as monohydrate.