Thermal inkjet application in the preparation of oral dosage forms: dispensing of prednisolone solutions and polymorphic characterization by solid-state spectroscopic techniques

The utility of thermal inkjet (TIJ) technology for preparing solid dosage forms of drugs was examined. Solutions of prednisolone in a solvent mixture of ethanol, water, and glycerol (80/17/3 by volume) were dispensed onto poly(tetrafluoroethylene)-coated fiberglass films using TIJ cartridges and a personal printer and using a micropipette for comparison. The post-dried, TIJ-dispensed samples were shown to contain a mixture of prednisolone Forms I and III based on PXRD analyses that were confirmed by Raman analyses. The starting commercial material was determined to be Form I. Samples prepared by dispensing the solution from a micropipette initially showed only Form I; subsequent Raman mapping of these samples revealed the presence of two polymorphs. Raman mapping of the TIJ-dispensed samples also showed both polymorphs. The results indicate that the solvent mixture used in the dispensing solution combined with the thermal treatment of the samples after dispensing were likely the primary reason for the generation of the two polymorphs. The advantages of using a multidisciplinary approach to characterize drug delivery systems are demonstrated using solid state mapping techniques. Both PXRD and Raman spectroscopy were needed to fully characterize the samples. Finally, this report clarifies prednisolone's polymorphic nomenclature existent in the scientific literature.     

Thermoanalytical and spectroscopic characterisation of solid-state retinoic acid

Thermoanalytical (differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), thermogravimetric analysis coupled with Fourier transform infrared spectroscopy (TG/FTIR)) and spectroscopic (X-ray diffraction (XRD), ultraviolet-visible (UV-Vis), mass spectrometry (MS) and Fourier transform infrared diffuse reflectance (DRIFT) measurements have been used to characterise solid-state retinoic acid (RA) from a chemico-physical point of view. Between 130 and 160 degrees C, a phase transition takes place that does not correspond to the transition between the known monoclinic and triclinic phases (DSC and XRD evidence). By annealing in air (in the 130-160 degrees C temperature range and for different times), an exothermic oxidative degradation occurs that, depending on the thermal treatment, competes with the mentioned phase transition (TGA evidence). Spectroscopic techniques (UV-Vis, MS and DRIFT) allow one to conclude that the new solid phase is still constituted by retinoic acid with a different orientation of the side chain. Finally, RA does not undergo stable melting: the fragmentation patterns, both in air and in nitrogen, have been examined by TG/FTIR.     

Characterization of solid-state forms of mebendazole

This study deals with the generation and characterization of various solid-state forms of mebendazole (MBZ), a benzimidazole antihelmentic. The drug was subjected to polymorphic screen using different solvents to explore the possibility of existence of different solid forms. Different reported polymorphic forms of MBZ, i.e. form A, B and C were found to be recrystallized from acetic acid:methanol mixture (1:1), ethyl acetate and methanol, respectively. N,N-Dimethyl acetamide (DMA) and N,N-dimethyl formamide (DMF) yielded two new solvates of MBZ. These solid-state forms were characterized by thermoanalytical (DSC, TGA, HSM), crystallographic (XRD), microscopic (optical, polarized), and spectroscopic (FTIR) techniques. Solubility studies were carried out for the solvates to identify the solubility advantage. Molecular modeling studies revealed moderately strong hydrogen bonding between the solvent molecules and MBZ.     

Physico-chemical solid-state characterization of omeprazole sodium: Thermal,spectroscopic and crystallinity studies

The physical characterization of active pharmaceutical substances is crucial to the successful development of the final drug product. The different solid forms and variations in the degree of crystallinity can lead to significantly different physical and chemical properties, including color, morphology, stability, dissolution and bioavailability. In the case of omeprazole sodium (OMS), its chemical structures contain a specific number of water molecules (hydrate). The behavior of pharmaceutical hydrates has become the object of increasing attention over the past decade, primarily due to the potential impact of hydrates on the development process and dosage form performance. The present study was designed to characterize and evaluate the crystallinity of omeprazole sodium, dehydrated omeprazole sodium (DOMS) and omeprazole free base (OM) using a variety of techniques including thermal analysis (thermogravimetry/derivative thermogravimetry (TG/DTG) and differential scanning calorimetry (DSC)), diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, scanning electron microscopy (SEM) and X-ray powder diffraction (XRPD). Furthermore, an NMR spectroscopy study was also carried out to clarify the conformation and crystal structure.     

Understanding the solid-state forms of fenofibrate - A spectroscopic and computational study

The aim of this study was to investigate the structure of different solid-state forms of fenofibrate, a drug that lacks strong intermolecular interactions such as hydrogen bonding. In addition to a structural analysis of crystalline and amorphous fenofibrate using infrared and Raman spectroscopy combined with density functional theory calculations [B3LYP 6-31G(d)], solid-state changes that occur upon recrystallization of amorphous fenofibrate were monitored and described using in situ Raman spectroscopy. A comparison of the calculated vibrational spectra of a fenofibrate monomer and two dimer structures with the experimental vibrational spectra of crystalline and amorphous fenofibrate revealed conformational differences in the orientation of the two benzyl rings in the fenofibrate molecule and structural differences between the different solid-state forms in aliphatic parts of the drug molecule. The spectroscopic analysis suggests that non-hydrogen-bonded drug molecules are likely to exhibit more random molecular orientations and conformations in the amorphous phase since the weak intermolecular interactions that occur between such molecules can easily be disrupted. In situ Raman spectroscopy and multivariate analysis revealed multiple solid-state forms of fenofibrate, including the metastable crystalline form II, which were structurally analyzed with reference to the quantum chemical calculations. Overall, the study showed that vibrational spectroscopy, multivariate analysis, and quantum chemical modeling are well suited to investigate and characterize the structure of drug substances that exhibit only small structural differences between different solid-state forms.     

Characterization of solid-state forms of celecoxib.

This study deals with the generation and characterization of various solid-state forms of celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor. The drug was subjected to polymorphic screen using different solvents to explore the possibility of existence of different solid forms. N,N-Dimethyl acetamide (DMA) and N,N-dimethyl formamide (DMF) yielded solvates in 1:1 stoichiometric ratio. Quench cooling of the melt resulted in amorphous form of the drug. All these solid-state forms were characterized by thermoanalytical (DSC, TGA, HSM), crystallographic (XRD), microscopic (polarized, SEM), spectroscopic (FTIR), and elemental analysis techniques. Solubility and van't Hoff studies were carried out for their thermodynamic interpretation. Influence of morphology of different solid-state forms on flow behavior was also investigated. Molecular modeling studies were used to elucidate the interaction between solute and solvent molecules in the solvate.     

Advanced microscopy techniques to assess solid-state properties of inhalation medicines

Efficient control and characterisation of the physico-chemical properties of active pharmaceutical ingredients (APIs) and excipients for orally inhaled drug products (OIDPs) are critical to successful product development. Control and reduction of risk require the introduction of a material science based approach to product development and the use of advanced analytical tools in understanding how the solid-state properties of the input materials influence structure and product functionality. The key issues to be addressed, at a microscopic scale, are understanding how the critical quality attributes of input materials influence surface, interfacial and particulate interactions within OIDPs. This review offers an in-depth discussion on the use of advanced microscopy techniques in characterising of the solid-state properties of particulate materials for OIDPs. The review covers the fundamental principles of the techniques, instrumentation types, data interpretation and specific applications in relation to the product development of OIDPs.     

Characterization of different samples of quercetin in solid-state: indication of polymorphism occurrence

The present work was designed to compare four commercial samples of quercetin, three of them presenting pharmaceutical grade (QPGa, QPGb and QPGc) and the other one pro-analysi grade (QPA) by means of different techniques. Physical and chromatographic characterization of these samples shows different properties following its origin, especially a clear evidence of polymorphism occurrence.     

Comparison and combination of spectroscopic techniques for the detection of counterfeit medicines

During this study, Fourier transform infrared spectroscopy (FT-IR), near infrared spectroscopy (NIR) and Raman spectroscopy were applied to 55 samples of counterfeit and imitations of Viagra^® and 39 samples of counterfeit and imitations of Cialis^®. The aim of the study was to investigate which of these techniques and associations of them were the best for discriminating genuine from counterfeit and imitation samples. Only the regions between 1800–400 cm⁻¹ and 7000–4000 cm⁻¹ were used for FT-IR and NIR spectroscopy respectively. Partial least square analysis has been used to allow the detection of counterfeit and imitation tablets. It is shown that for the Viagra^® samples, the best results were provided by a combination of FT-IR and NIR spectroscopy. On the other hand, the best results for the Cialis^® samples were provided by the combination of NIR and Raman spectroscopy (1400–1190 cm⁻¹). These techniques not only permitted a clear discrimination between genuine and counterfeit or imitation samples but also the distinction of clusters among illegal samples. This might be interesting for forensic investigations by authorities.     

Characterization of polymorphic solid-state changes using variable temperature X-ray powder diffraction

The aim of this study was to use variable temperature X-ray powder diffraction (VT-XRPD) to understand the solid-state changes in the pharmaceutical materials during heating. The model compounds studied were sulfathiazole, theophylline and nitrofurantoin. This study showed that the polymorph form of sulfathiazole SUTHAZ01 was very stable and SUTHAZ02 changed as a function of temperature to SUTHAZ01. Theophylline monohydrate changed via its metastable form to its anhydrous form during heating and nitrofurantoin monohydrate changed via amorphous form to its anhydrous form during heating. The crystallinity of SUTHAZ01, SUTHAZ02 and theophylline monohydrate were very high and stable. Nitrofurantoin monohydrate was also very crystalline at room temperature but during heating at lower temperatures the crystallinity decreased and started to increase strongly at the temperature where the sample had changed to the anhydrous form. The average crystallite size of sulfathiazole samples varied only a little during heating. The average crystallite size of both theophylline and nitrofurantoin monohydrate decreased during heating. However, the average crystallite size of nitrofurantoin monohydrate returned back to starting size at higher temperatures. These analyses showed that VT-XRPD can be used to effectively characterize polymorphic changes during heating.     

UV-vis and FTIR-ATR spectroscopic techniques to study the inclusion complexes of genistein with beta-cyclodextrins

The effect of beta-cyclodextrin (beta-CyD), (2-hydroxypropyl)-beta-cyclodextrin (HP-beta-CyD) and methyl-beta-cyclodextrin (Me-beta-CyD) complexation on the UV absorption of genistein (Gen) was studied in pure water. A phase solubility study was performed, according to the method reported by Higuchi and Connors, to evaluate the changes of isoflavone in the complexation state and the obtained diagrams suggested that it forms complexes with a stoichiometry of 1:1. Then, the solid complexes of genistein with these macrocycles in 1:1 molar ratio were prepared by the co-precipitation method and characterized by FTIR absorption spectroscopy in ATR geometry. The host-guest interactions have been evidenced by monitoring, in the FTIR-ATR spectra, the changes in some guest molecule bands relative to those observed in the spectra of the 1:1 physical mixtures and complexes. In particular, for the high-frequency O-H stretching band, a quantitative vibrational assignment of the observed sub-bands has been made. From the results, the inclusion phenomena have been discussed.     

Detection and characterization of cyclodextrin complexes with beta-carboline derivatives by spectroscopic techniques

beta-Carboline alkaloids exhibit a great variety of pharmacological activities. The solid inclusion complexes of harmane and harmine with beta-cyclodextrin and also with hydroxypropyl-beta-cyclodextrin, have been prepared following different procedures. IR and NMR spectroscopies were employed to verify the interaction of the guest molecules with the cyclodextrin cavities. The differences observed in the IR and NMR spectra are in agreement with those described in the literature for other guest molecules. The shifts in the 13C- and 1H-NMR spectra confirm the existence of the inclusion complexes. The fluorescence emission spectra of these complexes dissolved in buffered aqueous solution (pH 7.3) exhibit the characteristic peaks of the cationic form for harmane alkaloids. The neutral bands are not present for the free alkaloids in aqueous solutions. Fluorescence quenching emission of the complexes is compared to that of the corresponding free alkaloids.     

Investigational study of tamoxifen phase I metabolites using chromatographic and spectroscopic analytical techniques

A comprehensive overview is presented of currently known phase I metabolites of tamoxifen consisting of their systematic name and molecular structure. Reference standards are utilized to elucidate the MS(n) fragmentation patterns of these metabolites using a linear ion trap mass spectrometer. UV-absorption spectra are recorded and absorption maxima are defined. Serum extracts from ten breast cancer patients receiving 40mg tamoxifen once daily were qualitatively analyzed for tamoxifen phase I metabolites using a liquid chromatography-tandem mass spectrometry set-up. In total, 19 metabolites have been identified in these serum samples. Additionally a synthetic method for the preparation of the putative metabolite 3',4'-dihydroxytamoxifen is described.     

The binding affinity of phthalate plasticizers-protein revealed by spectroscopic techniques and molecular modeling

Phthalate plasticizers have been subjected to close scrutiny and evidences of their toxicity and other negative environmental impacts have arisen as a result of their use in food in some countries. Once entering human body, plasticizers could affect the conformation of human serum albumin and protein function. The interaction between two phthalate plasticizers and human serum albumin was investigated by multispectroscopic techniques and molecular modeling. The alteration in protein conformational stability was determined by fluorescence quenching data. The thermodynamic parameters indicated that the hydrophobic interactions played a major role in the process. In addition, the alterations of HSA secondary structure in the presence of phthalate plasticizers were investigated. Molecular modeling and displacement experiments showed that phthalate plasticizers situated within subdomain IIA (site I) of HSA. Furthermore, the binding distances for the plasticizers−HSA system were provided by the efficiency of fluorescence resonance energy transfer.     

Characterization of prednisolone in controlled porosity osmotic pump pellets using solid-state NMR spectroscopy

The overall objective of this study was to demonstrate the influence of formulation and processing variables on the physical state of prednisolone (PDL) in formulations consisting of PDL, microcrystalline cellulose (MCC), and sulfobutylether-beta-cyclodextrin (CD). PDL was used as a model drug in controlled porosity osmotic pump pellet (CP-OPP) formulations, and was characterized using solid-state NMR spectroscopy and other complimentary analytical techniques. Dosage forms and the solid-state properties of drugs and excipients in a formulation may be influenced by the processing conditions used. Several processing parameters, such as amount of water used in wet granulation and subsequent drying conditions, were found to affect the solid-state transformation of PDL. In addition, the presence of excipients in the CP-OPP was observed to decrease the degree of PDL crystallinity, presumably by creating an inclusion complex with the CD. A hydrated form of PDL was created when PDL was ground with water alone; however, this form was not observed in formulated products. Solid-state NMR spectroscopy was shown to be a powerful technique for the analysis of drug formulations and investigations of the effects of processing conditions.     

Estimation of the two sample preparation techniques for infrared spectroscopic identification of Cefamandole nafate in solid state

The European Pharmacopoeia (Ph.Eur.) monograph for Cefamandole Nafate (CFN) and the revised monograph prescribe the identification of the antibiotic in solid state by infrared (IR) absorption spectrophotometry using potassium bromide (KBr) disc technique. But, this technique may cause unwanted solid-solid transformations in the crystalline structure of the beta-lactam antibiotic CFN. The latter is a drug with proven polymorphism/pseudopolymorphism. In this context we have examined the suitability of the two techniques (KBr disc and Nujol mull) for IR spectral analyses to identify the antibiotic CFN in solid state. The results of our examinations show that KBr disc technique alters the crystalline state of CFN during the preparation of its KBr disc samples by the tribomechanical treatments (grinding and compression pressure). On the contrary, the Nujol mull technique does not cause such transformations and it is estimated as a better, more suitable technique to be employed for identification of CFN. For a greater precision, in solving the possible difficulties due to the KBr disc technique a second record of IR spectra is necessary to be provided by the Nujol mull technique with use of an internal standard (the stretching vibration of vC = 0 of the condensed beta-lactam cycle).     

Characterization of a novel polymeric prodrug of an antibacterial agent synthesized by mechanochemical solid-state polymerization

Polycrystalline methacryloyl monomers of the antibacterial drug nalidixic acid with an anhydride bond to the drug carboxyl group were prepared. The physicochemical properties of the synthesized vinyl monomer were characterized using X-ray powder diffraction, thermal analysis, and polarized light microscopy measurements. Mechanochemical solid-state polymerization of the resulting monomers was carried out to yield a novel polymeric prodrug. The in vitro hydrolysis behavior of the polymeric prodrug indicated that the release rate of drug from the polymeric prodrug was clearly dependent on the pH value of the hydrolysis solution. Moreover, sustained release of the drug at an almost constant rate for more than 10 hr was shown in both neutral and alkaline solutions. The results suggest that anhydride-based polymeric prodrugs could be potentially useful in colon targeted drug delivery systems.     

A comparison of reflectance and transmittance near-infrared spectroscopic techniques in determining drug content in intact tablets

Drug contents of intact tablets were determined using non-destructive near infrared (NIR) reflectance and transmittance spectroscopic techniques. Tablets were compressed from blends of Avicel PH-101 and 0.5% w/w magnesium stearate with varying concentrations of anhydrous theophylline (0, 1, 2, 5, 10, 20 and 40% w/w). Ten tablets from each drug content batch were randomly selected for spectral analysis. Both reflectance and transmittance NIR spectra were obtained from these intact tablets. Actual drug contents of the tablets were then ascertained using a UV-spectrophotometer at 268 nm. Multiple linear regression (MLR) models at 1116 nm and partial least squares (PLS) calibration models were generated from the second derivative spectral data of the tablets in order to predict drug contents of intact tablets. Both the reflectance and the transmittance techniques were able to predict the drug contents in intact tablets over a wide range. However, a comparison of the results of the study indicated that the lowest percent errors of prediction were provided by the PLS calibration models generated from spectral data obtained using the transmittance technique.